Front. Immunol. Frontiers in Immunology Front. Immunol. 1664-3224 Frontiers Media S.A. 10.3389/fimmu.2026.1759658 Review From microtubule remodeling to clinical translation: the multifaceted roles of vasohibin-1 in disease modulation WeiKeke 1 † Data curation Methodology Supervision Writing – original draft Software Conceptualization Investigation Resources Formal analysis Validation Writing – review & editing Project administration Visualization LiHui 1 † Data curation Validation Project administration Formal analysis Conceptualization Resources Supervision Writing – review & editing Writing – original draft Software Visualization Methodology HuangHuiquan 1 Visualization Data curation Supervision Project administration Conceptualization Writing – original draft Writing – review & editing Resources Formal analysis BanYinyan 1 Investigation Visualization Formal analysis Software Writing – review & editing Supervision Writing – original draft Validation LuoXiangbin 2 Project administration Writing – review & editing Validation Investigation Writing – original draft Formal analysis Resources Visualization ZhangChaoren 3 Validation Resources Writing – review & editing Investigation Visualization Writing – original draft Project administration GuoJian 1 Writing – review & editing Resources Formal analysis Investigation Visualization Writing – original draft Project administration TanMinghua 1 Project administration Writing – review & editing Investigation Writing – original draft Visualization Formal analysis Validation QinMinzhen 4 * Supervision Data curation Writing – original draft Visualization Conceptualization Project administration Writing – review & editing Validation Formal analysis Department of Critical Care Medicine (Ward 1), Baise People’s Hospital, Affiliated Southwest Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China Division 1, Department of General Surgery, People’s Hospital of Longlin Various Nationalities Autonomous County, Baise, Guangxi, China Department of Internal Medicine (Unit 1), People’s Hospital of Longlin Various Nationalities Autonomous County, Baise, Guangxi, China Department of Gastroenterology, Baise People’s Hospital, Affiliated Southwest Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China Correspondence: Minzhen Qin, qinminzhen@ymun.edu.cn

These authors have contributed equally to this work

 09 02 2026 2026 17 1759658 03 12 2025 19 01 2026 07 01 2026 Copyright © 2026 Wei, Li, Huang, Ban, Luo, Zhang, Guo, Tan and Qin. 2026 Wei, Li, Huang, Ban, Luo, Zhang, Guo, Tan and Qin https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Vasohibin-1 (VASH-1) is an endothelial protein that serves as a negative feedback regulator of angiogenesis. Through its microtubule carboxypeptidase activity, VASH-1 plays a key role in vascular homeostasis. While previous studies have investigated its involvement in vascular regulation, most have focused on isolated functions or specific disease models, without systematically addressing its multi-dimensional regulatory mechanisms, tissue-specific functional paradoxes, and translational potential. This review provides a comprehensive analysis of VASH-1’s biological characteristics: its expression is induced by pro-angiogenic factors, and it forms a functional complex with SVBP. In pathological contexts, VASH-1 exhibits paradoxical expression patterns—downregulated in neuroendocrine tumors but upregulated in bladder cancer—and demonstrates tissue-specific functions that either inhibit or promote angiogenesis. Clinically, VASH-1 serves both as a diagnostic marker (e.g., serum biomarker and tissue-based prognostic indicator) and a therapeutic target (such as improving renal disease or promoting tumor vascular normalization). This review aims to elucidate the complex physiological and pathological roles of VASH-1, providing a foundation for future precision intervention strategies targeting VASH-1 in disease diagnosis and therapy.

 Graphical Abstract

Diagram illustrating the roles of VASH-1 in disease modulation. Center features VASH-1 structure. Top left: Microtubule remodeling with α-tubulin detyrosination. Top right: Angiogenesis regulation with endothelial cells and vascular homeostasis. Bottom left: Disease modulation showing cancer, renal diseases, and autoimmune disorders. Bottom right: Clinical translation highlighting biomarkers and therapeutic targets.

angiogenesis regulation functional paradox microtubule carboxypeptidase targeted therapy vasohibin-1 The author(s) declared that financial support was not received for this work and/or its publication. section-at-acceptance Inflammation Introduction

The dynamic equilibrium of angiogenesis is maintained through the precise orchestration of endogenous regulatory networks. Vasohibin-1 (VASH-1), an autocrine negative feedback regulator secreted by endothelial cells, has become a central focus in vascular biology due to its unique functional triad: angiogenesis inhibition, microtubule remodeling, and fibrosis regulation. Its expression is controlled by a multi-tiered regulatory network: VEGF induces transcription via the VEGFR2/PKCδ/ERK axis (1, 2), while miRNAs such as miR-10a/b suppress translation (3). Functionally dependent on heterodimerization with SVBP, VASH-1 mediates α-tubulin detyrosination through its microtubule carboxypeptidase activity (4, 5), thereby modulating cytoskeletal stability and angiogenic signal transduction (6).

Beyond classical vascular regulation, VASH-1 is involved in a range of physiological processes, including vascular maturation, where it is enriched in the termination zones of nascent vessels to promote stabilization (7), multi-organ protection by inhibiting the TGF-β/Smad3 pathway to mitigate renal fibrosis (8), and immune microenvironment remodeling through suppression of NF-κB signaling to reduce inflammatory infiltration (9). Notably, VASH-1 exhibits tissue-specific functional paradoxes, such as pro-angiogenic activity in diabetic tissues (10) and dynamic responsiveness to vascular demands in skeletal muscle (11).

Studies on disease association reveal paradoxical expression patterns: systemic downregulation in neuroendocrine tumors (12) contrasts with a positive correlation with aggressiveness in bladder cancer (13). In colorectal cancer (CRC), spatial heterogeneity between tumor cells and stroma leads to functional reversal (14, 15). The clinical translational value of VASH-1 is further highlighted by its role as a serum biomarker for pre-eclampsia risk assessment (16), adenovirus-delivered therapy for ameliorating diabetic nephropathy (DN) (17), and spatiotemporally controlled vascular normalization achieved through sonoporation (18).

This review explores the molecular regulatory network of VASH-1, its disease-specific functional reprogramming, and the challenges to clinical translation, with a focus on organ-targeted delivery systems and multi-omics-integrated strategies to elucidate its microenvironment-dependent functional plasticity.

 Biological characteristics of vasohibin-1 Molecular origin and basic features

VASH-1 is an endogenous protein encoded by a gene located on human chromosome 14q24.3 (19). The gene spans approximately 13 kb of genomic DNA, consisting of eight exons, and transcribes a 5,589-base-pair mRNA, which encodes a 365-amino-acid protein with a molecular weight of approximately 44 kDa (20). VASH-1 expression is tightly regulated at multiple levels: Transcriptional regulation involves positive regulators like VEGF through the VEGFR2/PKCδ/ERK axis (1, 2, 21) and lncRNA H19, which counteracts EZH2-mediated promoter methylation (22). In contrast, negative regulation is exerted by miRNAs (e.g., miR-10a/b, miR-143-3p, and miR-221-3p), which target the mRNA’s 3’UTR to suppress translation (3, 23, 24), EZH2-mediated epigenetic silencing through promoter methylation (25), and the transcriptional repressor ZNF667 (26). Post-translational regulation includes modulation of stability and activity through heterodimerization with SVBP, which protects VASH-1 from ubiquitin-mediated degradation, maintaining its catalytic function (4). Additionally, calcium-dependent calpain pathways influence its enzymatic activity (27). Alternative splicing generates isoforms with distinct functions: full-length VASH1A (365 aa) primarily regulates vascular normalization and chemosensitization (18), while truncated VASH1B (204 aa) enhances anti-angiogenic activity and induces autophagic cell death in endothelial cells (18, 28).

 Core biological functions

VASH-1 performs a wide range of biological functions, with its central role being anti-angiogenesis. As an autocrine negative feedback regulator, it inhibits endothelial cell proliferation and migration induced by VEGF, FGF, and PDGF through paracrine signaling (1, 21). VASH-1 is notably enriched in the termination zones of nascent vessels, promoting vascular maturation and stabilization (7). Its expression level, particularly the VASH-1/CD31 ratio, serves as an indicator of neovascular density in tumors, such as neuroendocrine tumors, and correlates positively with the proliferation marker Ki-67 (29, 30). In addition to angiogenesis regulation, VASH-1 is involved in several other critical processes: Anti-fibrosis and organ protection, where it inhibits TGF-β-dependent renal fibroblast activation, reduces collagen deposition (8), preserves glomerular filtration barrier integrity (31), and suppresses endothelial-to-mesenchymal transition (EndMT) in retinal endothelial cells (32); Microtubule dynamics regulation, where as a tubulin carboxypeptidase (TCP), the VASH-1/SVBP complex catalyzes α-tubulin detyrosination, modulating cytoskeletal stability (5, 33), and indirectly blocking angiogenic signaling by inhibiting VEGFR2 endocytic trafficking (6); Inflammation and immune modulation, by downregulating the nuclear translocation of NF-κB pp65 and CCL2 expression, reducing monocyte/macrophage infiltration (9). In rheumatoid arthritis synovium, VASH-1 expression is dynamically regulated by inflammatory factors (34). Tumor microenvironment modulation is another significant function, where VASH-1 inhibits ovarian cancer cell migration (35) and reverses chemotherapy resistance in osteosarcoma by suppressing P-glycoprotein (P-gp) expression (36). VASH-1 exhibits tissue-specific and paradoxical functions, such as pro-angiogenic activity in diabetic penile tissue (10) and vascular demand-responsive expression in skeletal muscle (p36/42 isoforms). Under hypovascularized conditions, high expression of VASH-1 suppresses excessive angiogenesis, while post-exercise downregulation permits adaptive neovascularization (11).

 Core molecular mechanisms of function

VASH-1’s diverse functions are driven by its enzymatic activity and critical regulation of key signaling pathways. At the core of its mechanism is its TCP activity: the VASH-1/SVBP heterodimer, dependent on the conserved Cys-His-Ser catalytic triad, specifically hydrolyzes the C-terminal tyrosine residue of α-tubulin (37). This enzymatic function directly: maintains podocyte microtubule integrity for renal protection (31) and disrupts VEGFR2 endocytosis and recycling to inhibit pro-angiogenic signaling (6). At the signaling pathway level, VASH-1 exerts broad effects via: Anti-fibrosis, by blocking Smad3 phosphorylation to inhibit TGF-β/Smad3 signaling and reduce collagen synthesis (8, 9); Anti-inflammation, by suppressing NF-κB pp65 nuclear translocation to downregulate pro-inflammatory genes (9); Chemoresistance reversal, through activation of AKT signaling to suppress P-gp expression (36); Cell death regulation, by inhibiting ferroptosis (via GPX4 upregulation) (38) or promoting protective mitophagy (via PINK1/Parkin pathway disruption) (39), with context-dependent effects. Tissue-specific microenvironments dynamically modulate VASH-1’s functional outputs, such as pro-angiogenic effects in diabetic penile tissue (10) and bidirectional vascular regulation by distinct isoforms (e.g., p36/p42) in muscle tissue (11).

In summary, VASH-1 synthesis, stability, and function are controlled by a tripartite regulatory network involving gene expression, protein interactions, and signaling pathways. Its pleiotropic biological functions—anti-angiogenesis, organ protection, microtubule remodeling, and inflammation modulation—are rooted in its core enzymatic activity and its deep integration with key signaling cascades, including TGF-β, NF-κB, and AKT. The dynamic remodeling of VASH-1’s functional phenotype by tissue-specific microenvironments not only highlights its biological complexity but also provides key theoretical frameworks and intervention opportunities for developing precision therapeutics targeting VASH-1 (Figure 1).

Molecular mechanism of Vasohibin-1. The figure conceptually outlines the molecular mechanism of VASH-1 in a hierarchical manner: Upper layer: the genetic origin and multi-level regulation of VASH-1 expression; Middle layer: the core biological functions of the VASH-1 protein, which depend on SVBP binding; Lower layer: key intracellular signaling pathways (TGF-β/Smad3, NF-κB, AKT) and molecular processes (microtubule dynamics) that mechanistically link VASH-1 activity to its observed functions.

Diagram illustrating the regulation and function of the VASH-1 gene. It details gene expression on chromosome 14q24.3, producing a protein regulated by VEGF, lncRNA H19, miRNAs, and EZH2. The VASH-1 protein binds SVBP, influencing anti-angiogenesis, organ protection, microtubule regulation, and immune modulation. Cellular pathways include TGF-beta/Smad3, NF-kB signaling, AKT pathway, and microtubule dynamics. Expression profile and functional regulation of VASH-1 in diseases Tumor diseases: from paradoxical expression to precision classification Neuroendocrine neoplasms

Neuroendocrine Neoplasms (NENs): VASH-1 is systematically downregulated in NENs, with serum levels (218.8 pg/mL) significantly lower than in healthy controls (973.1 pg/mL). Pancreatic NENs show higher expression compared to other subtypes (12). Within the tumor microenvironment, VASH-1 accumulates in neovascular endothelial cells, and the VASH-1/CD31 ratio increases with higher WHO malignancy grades (29). Notably, neuroendocrine regions exhibit significantly stronger VASH-1 expression than non-neuroendocrine areas (p < 0.0001), inversely correlating with serotonin levels (r = −0.19), suggesting VASH-1’s role in suppressing pathological angiogenesis and neuroendocrine activity (12, 40).

 Bladder cancer and gastric cancer

Bladder Cancer: VASH-1 is overexpressed in both tumor cells and vascular endothelium in bladder cancer, positively correlating with advanced stage (pT3-4), high pathological grade (G3), and distant metastasis (P < 0.01) (13). Paradoxically, high microvessel density (≥40/mm²) predicts chemotherapy sensitivity and improved survival (5-year recurrence-free survival: 66.3% vs 33.3%) (41). Its expression is dynamically regulated by the hypoxia-HIF-1α-VEGF axis: hypoxia downregulates VASH-1 in cancer cells, while tumor-associated macrophages (TAMs) reverse this suppression (42).

Gastric Cancer: In gastric cancer, VASH-1 positivity in tumor cells correlates with lymphovascular invasion (Ly+), advanced T-stage, and poor prognosis (43). TAMs upregulate VASH-1 expression via TGF-β/BMP signaling, thereby promoting angiogenesis and an immunosuppressive microenvironment (44, 45).

 Dual roles in breast and ovarian cancers

Breast Cancer: VASH-1 expression influences therapeutic responses: higher VASH-1 positivity rates (VPR) correlate with sensitivity to endocrine therapy (46), while low expression in triple-negative breast cancer (TNBC) predicts pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) (47). miR-4530-mediated suppression of VASH-1 promotes angiogenesis (48).

Ovarian Cancer: VASH-1 exhibits paradoxical roles: Tumor-suppressive: Low tissue expression correlates with poor prognosis, and its paracrine secretion inhibits endothelial migration and proliferation (2, 49). Pro-tumorigenic: In serous carcinoma, VASH-1 strongly correlates with the metastasis gene MACC1 (r = 0.518), serving as an independent poor prognostic factor (RR = 2.185) (50). Targeting VASH-2 enhances paclitaxel sensitivity (51).

 Spatial paradox in hepatocellular and colorectal cancers

(1) HCC: In HCC, VASH-1 positivity is higher in tumor tissue (38.5%) compared to adjacent tissue (16.2%), correlating with microvascular invasion (P = 0.02) and shorter survival (HR = 2.554) (52, 53). Cancer-associated fibroblasts (CAFs) epigenetically silence VASH-1 via the VEGF-EZH2 axis to promote angiogenesis (54).

(2) CRC: VASH-1’s role in CRC depends on its spatial localization: Pro-metastatic: High cytoplasmic expression in cancer cells promotes advanced metastasis (14, 55). Anti-metastatic: High stromal expression suppresses metastasis (15). The circASS1/miR-1269a axis targets VASH-1 for suppression (56).

Summary: VASH-1 exhibits microenvironment-dependent functionality in tumors: Protumorigenic overexpression occurs in HCC and bladder cancer, driven by the hypoxia-HIF-1α axis, while anti-tumorigenic expression is observed in ovarian cancer through paracrine endothelial suppression and in CRC stroma. Spatially, cancer cells typically promote progression, whereas the stroma may inhibit metastasis. As a circulating biomarker, low serum levels assist in NEN diagnosis, while elevated plasma levels are associated with reduced mortality risk in non-small cell lung cancer (NSCLC) (12, 57) (Table 1).

Common patterns in other tumors.

Tumor type Core finding Key mechanism Clinical trial Refs
Osteosarcoma Low tumor expression → doxorubicin resistance AKT-P-gp pathway inhibition Not specified (36)
NSCLC High tissue expression → poor prognosis; High plasma levels → ↓mortality miR-143-3p targeting Yes; n = 79 (57)
Esophageal cancer High cancer cell expression → ↓tumor volume; High plasma levels → ↑lymph node metastasis Direct proliferation/migration inhibition Yes; n = 100 (58)
Prostate cancer Ductal adenocarcinoma > acinar adenocarcinoma expression → Gleason upgrade, ↓survival Undefined Yes; n = 34 (59)
HNSCC High tumor/endothelial expression → ↑lymph node recurrence, ↓survival Undefined Yes; n = 61 (60)
LAM Correlates with VEGFR2/MMP9/p-mTOR Pro-angiogenic Yes; n = 36 (61)

The symbol → indicates that A causes B, ↓ indicates downregulation (decreased expression), and ↑ indicates upregulation (increased expression).

 Immunological disorders: guardian of vascular homeostasis Systemic sclerosis

SSc is a multisystem autoimmune disease characterized by widespread small-vessel vasculopathy and damage, accompanied by activation of skin and organ fibrosis (62). It involves a complex interplay of vasculopathy, inflammation, and fibrosis (63). In SSc, serum VASH-1 levels are significantly elevated (P < 0.01) and positively correlate with modified Rodnan skin thickness scores (mRSS; r = 0.48), with higher concentrations observed in diffuse cutaneous SSc (dcSSc) and patients with interstitial lung disease (8). Mechanistically, VASH-1 inhibits fibroblast activation by suppressing the TGF-β/Smad3 pathway, reducing collagen I/III deposition, and establishing an anti-fibrotic feedback loop.

 Atopic dermatitis

AD is an inflammatory skin disease affecting up to 20% of children and 5% of adults (64). Genetic factors involved include those related to skin-barrier formation (e.g., filaggrin gene mutations), epidermal enzyme activity, lipid metabolism, and immune-system regulation (65). Patients with AD exhibit significantly higher serum VASH-1 levels than healthy controls (P < 0.001), with specific endothelial overexpression in lesional skin (66). VASH-1 expression correlates positively with disease duration and lesional VEGF-A levels (r = 0.72), suggesting a role in negative feedback regulation of VEGF-driven angiogenesis to maintain chronic inflammatory homeostasis. This mechanism requires further validation.

 Rheumatoid arthritis

RA is a heterogeneous, prevalent, and chronic autoimmune disease characterized by joint pain, swelling, and significant disability (67). In RA, inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis, leading to joint destruction (68). RA is associated with immune-system dysregulation and persistent inflammation (69).

VASH-1 is highly expressed in synovial lining fibroblasts and pannus endothelium of patients with RA (34). Expression during active disease exceeds that during remission and strongly correlates with synovitis scores (r = 0.842). Induced by VEGF, TNF-α, and IL-6, VASH-1 forms a negative feedback loop to constrain pathological pannus expansion.

 Other diseases: trans-organ protection and dysregulation Renal diseases

(1) DKD is the most common microvascular complication of both type 1 and type 2 diabetes, now surpassing glomerulonephritis as the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) (70). Its pathogenesis involves synergistic metabolic, hemodynamic, inflammatory, and fibrotic pathways. Renal tissue VASH-1 expression is reduced and correlates positively with renal impairment, while serum levels increase with worsening proteinuria (71–73). Mechanistically, intrarenal VASH-1 deficiency reduces podocyte α-tubulin detyrosination, disrupting the filtration barrier (31). (2) Renal fibrosis is a common terminal pathological manifestation in the progression of CKD (74) and is a key independent risk factor for CKD progression and poor prognosis (75). In fibrosis, VASH-1 suppression by miR-10a/b targeting promotes Smad3 phosphorylation, exacerbating collagen deposition (3). (3) CKD: Renal VASH-1 is upregulated and localizes to glomerular endothelia, mesangial cells, and interstitial infiltrating polymorphonuclear neutrophils (PMNs). Its density correlates with crescent formation (r = 0.64) and interstitial inflammation scores. Elevated plasma and urinary VASH-1 levels predict rapid estimated glomerular filtration rate (eGFR) decline (76, 77).

 Metabolic and vascular diseases

(1) Diabetic Retinopathy (DR): DR, a common complication of diabetes and a leading cause of vision loss globally, can be prevented with early detection and intervention (78, 79). Serum VASH-1 concentrations follow a gradient: healthy controls < non-proliferative DR < proliferative DR (P < 0.05), positively correlating with body mass index (BMI) and glycated hemoglobin (HbA1c) (80). The flavonoid kaempferol protects retinal ganglion cells through the ERK/VASH-1 axis (81). (2) Cardiovascular Diseases: In heart failure, myocardial VASH-1 expression predominates (exceeding VASH-2 by more than 10-fold), mediating mitochondrial respiratory dysfunction (39, 82). Atherosclerotic plaque neovessels show high VASH-1 expression, which correlates with VEGFA (r = 0.788) and VCAM1 (r = 0.94) (83). (3) Pulmonary Hypertension (PAH) & Idiopathic Pulmonary Fibrosis (IPF): In PAH, elevated VASH-1 facilitates vascular remodeling, with an imbalanced VASH-2/VASH-1 ratio contributing to disease progression (84). In IPF, increased VASH-1 suppresses EndMT (85).

 Pregnancy and reproductive disorders

(1) Preeclampsia (PE): A common pregnancy-related complication, PE is a leading cause of maternal, fetal, and neonatal morbidity and mortality, with long-term adverse effects on both mother and offspring (86). First-trimester serum VASH-1 is significantly elevated (cutoff: 1314.73 pg/mL, AUC = 0.631) (16). Placental VASH-1 expression is induced by hypoxia-HIF-1α (87). (2) Placental Development: Endothelial VASH-1 inhibits fetal angiogenesis, while trophoblastic VASH-2 promotes syncytiotrophoblast fusion (88). (3) Erectile Dysfunction (ED): Affecting more than 50% of men over 40 years of age (89), ED, defined as the inability to achieve or maintain an erection firm enough for satisfactory sexual performance, is linked to risk factors such as hypertension, hypercholesterolemia, obesity, sedentary lifestyle, diabetes, and smoking (90). Diabetic cavernosal VASH-1 downregulation contributes to microvascular dysregulation (10). (4) Endometriosis: miR-143-3p-mediated suppression of VASH-1 promotes stromal cell invasion (91).

 Aging and injury repair

(1) Vascular Aging: Senescent endothelia show VASH-1 downregulation via miR-22-3p targeting (92). VASH1(−/−) mice exhibit increased lifespan, associated with reduced insulin resistance (93). (2) Age-Related Macular Degeneration (AMD): AMD, a degenerative disease causing central vision loss, is classified into dry (non-neovascular) and wet (neovascular) types (94). Hypoxia-induced downregulation of retinal pigment epithelium (RPE) VASH-1 promotes choroidal neovascularization through increased tRF-Glu-CTC expression (95). (3) Cerebral Ischemia-Reperfusion Injury: Vash1(+/-) mice show reduced infarct volume via upregulation of GPX4 (inhibiting ferroptosis) and downregulation of ACSL4 (reducing pro-ferroptotic signaling) (38). (4) Bronchiolitis Obliterans (BO): BO, an irreversible obstructive lung disease characterized by terminal bronchiole inflammation and fibrosis (96), follows a pathogenesis cascade of epithelial injury → aberrant inflammation → fibroproliferation → luminal obliteration (97). VASH-1 inhibits graft-associated pathological angiogenesis, attenuating tracheal fibrosis (21) Figure 2.

Schematic diagram of VASH-1 expression in various diseases. Horizontal bars indicate expression direction (↑ up-regulation, ↓ down-regulation) in the indicated disease entities; bar color denotes specimen source (tissue, serum, or spatial distribution). Data integrate oncologic (gastric, colorectal, HCC, prostate, etc.), metabolic-vascular (DKD, DR, CVD), obstetric (preeclampsia), fibro-inflammatory (SSc, IPF), reproductive, aging, and injury-repair contexts, highlighting the context-dependent and trans-organ protective/dysregulatory nature of VASH-1.

Expression and Functional Profile of VASH-1 in Human Diseases. A circular diagram illustrates VASH-1 expression in various diseases, categorized into tumor diseases, immunological disorders, renal and metabolic disorders, reprodictive disorders, and pregreatiaces. Red indicates upregulated expression, blue indicates downregulated expression, and green represents context-dependent or spatial paradox. Disease categories are detailed, including specific cancers and other tumors. Clinical translational value of vasohibin-1 (VASH-1): from diagnostic biomarker to precision intervention Tumor diseases: navigator for diagnostic stratification and therapeutic response Prognostic alert of tissue biomarkers

(1) In bladder cancer, a highly recurrent urological malignancy, immunohistochemistry was performed on 50 tumor specimens to assess the expression of VASH-1 and angiogenesis-related factors VEGF, HIF-1α, and CD34, correlating their levels with clinicopathological features. Elevated VASH-1 expression emerged as an indicator of aggressive phenotype, significantly associated with advanced stage (pT3-4), high grade (G3), and metastatic risk (P < 0.01), functioning as an independent marker of poor prognosis (13). (2) In gastric cancer, a study analyzed VASH-1 immunohistochemical expression in 210 patients who underwent radical gastrectomy, classifying them into VASH-1–positive and VASH-1–negative groups. VASH-1 positivity in cancer cells was strongly correlated with lymphovascular invasion (Ly+), T-stage progression, and reduced overall survival (43). (3) In HCC, a study evaluated the immunoreactivity of FGF-2 and VEGF-A, along with microvessel density (MVD-CD34) as defined by VASH-1 and CD34 expression in 181 patients with HCC, correlating these findings with clinical outcomes. Double immunostaining for CD34, VASH-1, and Ki-67 was conducted to assess the angiogenic activity of endothelial cells. A VASH-1/CD34 ratio >0.459 predicted microvascular invasion (53). (4) In ovarian serous carcinoma, immunohistochemical Elivision™ staining was used to detect VASH-1, MACC1, and KAI1 proteins in 124 serous ovarian cancer tissues and 30 serous cystadenoma controls. VASH-1 strongly correlated with the metastasis-associated gene MACC1 (r = 0.518) and served as an independent poor-prognostic factor (relative risk [RR] = 2.185) (50).

 Predictors of therapeutic response

(1) In a paradoxical study involving 40 Japanese patients with BCa who received NAC followed by radical cystectomy, immunohistochemical expression of CD34, VASH-1, and carbonic anhydrase 9 (CA9) was compared between tumors that achieved complete pathological clearance (ypT0) and those with residual disease. Within the bladder cancer microvasculature, high VASH-1 expression (≥ 40/mm²) predicted chemosensitivity, indicating achievement of ypT0 after NAC and correlating with a higher 5-year recurrence-free survival rate (66.3% vs 33.3%) (41). (2) In TNBC, a study performed dual immunohistochemistry on biopsy specimens to quantify CD8+ and FOXP3+ tumor-infiltrating lymphocytes, along with immunolabeling for VASH-1, CD31, EGFR, CK5/6, and Ki-67. Low tumor VASH-1 expression predicted a positive response to chemotherapy, achieving 78% sensitivity and 82% specificity for pCR, with the pCR rate in the low-expression cohort being 3.5-fold higher (47).

 Breakthrough value of circulating biomarkers

A total of 79 patients with lung cancer (51 men, 28 women; age range 34–83 years; 46 adenocarcinomas, 27 squamous cell carcinomas, and 6 other histologies) who underwent pulmonary resection were enrolled. Preoperative plasma VASH-1 concentrations were measured and correlated with clinical characteristics and prognosis. Patients with NSCLC whose preoperative plasma VASH-1 exceeded 1190.4 fmol/mL had a 58% reduction in death risk compared to those with lower levels, highlighting its potential as a non-invasive biomarker (57) Table 2.

Core diagnostic value of VASH-1 in tumors.

Tumor type Sample type Clinical significance Clinical trial Refs
Osteosarcoma Tumor tissue Low expression → ↑40% doxorubicin resistance Not specified (36)
Prostate ductal adenocarcinoma Tumor tissue High expression (density >45.1/mm²) → ↓30% 5-year survival Yes; n = 34 (59)
Cervical squamous cell carcinoma Lymphatic endothelium → ↑Lymph node metastasis risk (miR-221-3p targeting) Yes; n = 107 (24)
Esophageal squamous cell carcinoma Tumor tissue High expression → ↓5-year survival Yes; n = 209 (98)
HCC subtyping Tumor tissue Low expression → K19+ high-aggressiveness subtype → ↑metastasis risk Yes; n = 136 (99)
Non-tumor diseases: sentinel for early warning and disease monitoring Serum-dominated early-warning systems

(1) In PE, a prospective case-control study collected first-trimester blood from 1,054 pregnant women, including 43 who later developed PE and 129 controls randomly selected (1:3) from 777 uncomplicated pregnancies. Commercial ELISA kits quantified serum VASH-1, cardiotropin-1, and endocan. VASH-1 levels were significantly higher in the PE group (p = 0.010), with ROC analysis yielding an AUC of 0.631 (95% CI 0.53–0.72) and an optimal cut-off of 1,314.73 pg/mL (60% sensitivity, 60% specificity), providing an early window for high-risk intervention (16). (2) In DKD, 143 patients with type-2 DN were compared to 80 diabetes-without-nephropathy controls. Stratifying DN by UACR (micro-albuminuria 30–300 mg/g; macro-albuminuria ≥ 300 mg/g) showed that serum VASH-1 levels rose in parallel with increasing UACR, validating it as a dynamic biomarker of renal deterioration (p < 0.01) (72). (3) In SSc, clinical correlation of serum VASH-1 with its dermal expression revealed a significant association with the mRSS (r = 0.48), indicating its predictive value for diffuse cutaneous SSc and interstitial lung disease (8).

 Tissue-specific injury markers

(1) In ED, a study found that VASH-1, traditionally viewed as anti-angiogenic, significantly restored erectile function in diabetic mice. Compared to healthy controls, diabetic patients exhibited a 50% reduction in corporal VASH-1 expression, marking a threshold indicative of diabetic microangiopathy (10). (2) In RA, surgical synovial samples from patients with RA and osteoarthritis (OA) were examined by immunohistochemistry for VASH-1 distribution and correlated with synovial inflammation. In vitro, RA synovial fibroblasts (RASFs) stimulated with VEGF or pro-inflammatory cytokines under normoxia or hypoxia were analyzed by real-time PCR for VASH-1 and VEGF mRNA. High synovial VASH-1 expression strongly correlated with synovitis score (r = 0.842), positioning it as an activity biomarker of synovial inflammation (34) Table 3; Figure 3.

Extended diagnostic value in Non-tumor diseases.

Disease type Sample type Clinical significance Key mechanism Clinical trial Refs
Adolescent hypertension Circulating blood High expression → systolic BP correlation (r = 0.314) Early vascular injury marker Yes; n = 132 (100)
Coronary artery disease (CAD) Circulating EPCs Low expression → vascular repair dysfunction (miR-720 targeting) Endothelial repair warning Not specified (101)
Periodontitis Gingival tissue High expression → Pg-induced inflammatory response Pathogen response marker Not specified (102)
Hypertension target organ injury Circulating blood ↑Predictive power combined with miR-335-5p/HYAL1 Multi-marker synergy Yes; n = 132 (100)
Diabetic retinopathy Serum ↑ Staging marker (proliferative > non-proliferative) ↑Levels in the proliferative phase Yes; n = 162 (80)

Diagnostic value of VASH-1 in multiple diseases. Colored bars summarize its diagnostic or risk-stratifying value in malignancies (ovarian, gastric, NSCLC, bladder, HCC), obstetric (first-trimester preeclampsia), metabolic-microvascular (DKD, DR), fibro-inflammatory (SSc, RA) and reproductive (ED) disorders. Arrow direction (↑ or ↓) indicates whether high or low expression predicts poor outcome; adjacent numbers give AUC, sensitivity/specificity, relative risk or correlation coefficient. Sample source (tissue, serum, synovial fluid, cavernosal biopsy) is coded by bar shade, illustrating VASH-1’s utility as both a circulating early-warning sentinel and a tissue-specific injury marker.

Circular chart titled “Clinical Translational Value of VASH-1 Across Diseases,” divided into tumor diseases (60%) in red-orange and non-tumor diseases in blue. Tumor diseases include gastric cancer, ovarian cancer, and NSCLC. Non-tumor diseases include preeclampsia and systemic sclerosis. The chart also notes biomarker types: tumor diseases (red-orange), circulating biomarkers (medium gray), and both (dark gray). Therapeutic targets: from mechanism to clinical intervention Renal diseases: anti-fibrotic breakthroughs

(1) Acute Kidney Injury (AKI): VASH-1 activation in cisplatin-induced AKI preserves capillary density, resulting in a 40% reduction in inflammatory infiltration and a 60% reduction in tubular injury score (103). (2) DN: Adenovirus-delivered human VASH-1 (Ad-hVASH-1), administered intravenously, reduces VEGFR2 phosphorylation and TGF-β1/MCP-1 expression, leading to a 70% improvement in proteinuria (17). (3) Renal Fibrosis: Inhibition of miR-10a/b increases VASH-1 expression, preventing Smad3 phosphorylation and reducing collagen deposition by approximately 45% (3). These findings highlight the potential of VASH-1 as a therapeutic target in various renal disease models Figure 4.

VASH-1-mediated therapeutic mechanisms in renal diseases. The schematic shows three injury models: acute kidney injury (AKI), diabetic nephropathy (DN) and renal fibrosis. In AKI, activated VASH-1 maintains peritubular capillary density and lowers VEGFR2 phosphorylation, reducing inflammatory infiltration and tubular damage. In DN, Ad-hVASH-1 gene delivery suppresses VEGFR2 signaling and down-regulates TGF-β1/MCP-1, producing a 70% decrease in proteinuria. In fibrosis, blockade of miR-10a/b restores VASH-1 levels, prevents Smad3 phosphorylation and cuts collagen deposition by ~45%. Collectively, the figure illustrates VASH-1 as a multi-hit therapeutic target that simultaneously preserves microvasculature, antagonizes TGF-β/Smad3 signaling and attenuates extracellular-matrix accumulation in diverse renal pathologies.

Illustration showing mechanisms affecting renal fibrosis. Acute Kidney Injury (AKI) leads to VASH-1 activation, preserving capillary density. Diabetic nephropathy reduces VEGFR2 phosphorylation via Ad-hVASH-1. Inhibiting miR-10a/b increases VASH-1, blocking Smad3 phosphorylation. Tumor therapy: reversing resistance and vascular remodeling

(1) Osteosarcoma: VASH-1 overexpression combined with AKT inhibitor treatment reduces P-gp expression, enhancing doxorubicin accumulation and reversing resistance (IC50 reduced by approximately 50%) (36). (2) HCC: Targeting the CAFs-VEGF-EZH2 axis increases VASH-1 expression, inhibiting angiogenesis and reducing primary tumor volume by approximately 65% (54). (3) CRC: siRNA-mediated VASH-1 knockdown promotes anoikis, reducing liver metastases by approximately 70% (55). (4) NSCLC: Intravenous administration of adenovirus-delivered human VASH-1 (Ad-hVASH-1) enhances pericyte coverage, promoting vascular maturation. Combined with cisplatin, it suppresses tumor growth by approximately 80% in nude mice (104). (5) Ovarian Cancer: CRISPR-mediated VASH-2 knockout reduces microtubule detyrosination and increases cyclin B1 expression, enhancing paclitaxel sensitivity (IC50 reduced by approximately 40%) (51) Figure 5.

Multi-faceted therapeutic targeting of VASH-1 in cancer treatment. The panel illustrates five tumor models: osteosarcoma, HCC, CRC, NSCLC and ovarian cancer. Osteosarcoma: VASH-1 overexpression plus AKT inhibitor down-regulates P-glycoprotein, halves doxorubicin IC50; and re-sensitizes cells. HCC: Disruption of the CAF-VEGF-EZH2 axis boosts endogenous VASH-1, curtails neovascularization and shrinks primary tumors by ~65%. CRC: siRNA knock-down of VASH-1 triggers anoikis and reduces liver metastases by ~70%. NSCLC: Ad-hVASH-1 increases pericyte coverage, normalizes vessels and, combined with cisplatin, suppresses xenograft growth by ~80%. Ovarian cancer: CRISPR deletion of VASH-2 (functional counterpart) decreases microtubule detyrosination, elevates cyclin B1 and lowers paclitaxel IC50; by ~40%. Collectively, the figure portrays VASH-1 as a druggable node that can be either up-regulated or down-regulated to reverse chemo-resistance, re-engineer the tumor vasculature and improve therapeutic indices across divergent malignancies.

Diagram depicting cancer cell interactions with VASH-1, highlighting different cancer types: osteosarcoma, HCC, NSCLC, and colorectal cancer. Central illustration shows blood vessels with labeled effects, including VASH-1 overexpression in osteosarcoma and siRNA-mediated knockdown in colorectal cancer. Cardio-cerebrovascular protection

(1) Cerebral Ischemia: Vash1(+/-) inhibition upregulates GPX4 and downregulates ACSL4, inhibiting ferroptosis and reducing infarct volume by approximately 30% (38). (2) Heart Failure: VASH-1/SVBP knockdown reduces microtubule detyrosination, decreasing myocardial stiffness and improving diastolic function by approximately 35% (82). (3) Atherosclerosis: Local VASH-1 delivery reduces plaque neovascularization, lowering rupture risk by approximately 50% (83). These findings demonstrate the therapeutic potential of targeting VASH-1 in oncology and cardiovascular disease contexts Table 4; Figure 6.

VASH-1 intervention in fibrotic diseases.

Disease Intervention Core mechanism Efficacy Model Refs
Pulmonary fibrosis Gambogic acid ↑VASH-1/VASH-2 ratio → ↓TGF-β1/Smad3 ↓60% collagen deposition Bleomycin mice (85)
Portal hypertension Adenovirus-mediated VASH-1 OE Breaks the VEGF/VASH-1 negative feedback loop ↓40% portal pressure Cirrhotic rats (105)
Corneal neovascularization Subconjunctival Ad-VASH-1 ↓Vegfr2 expression → angiogenesis inhibition ↓50% neovascular area Alkali-burn rats (106)

Cardio-cerebrovascular protective effects of VASH-1 modulation. The panel depicts three injury scenarios: cerebral ischemia, heart failure and atherosclerosis. Cerebral ischemia: partial Vash1 knock-down up-regulates GPX4, down-regulates ACSL4, suppresses microtubule de-tyrosination-driven ferroptosis and cuts infarct volume by ~30%. Heart failure: VASH-1/SVBP silencing decreases microtubule de-tyrosination, reduces myocardial stiffness and improves diastolic function by ~35%. Atherosclerosis: local VASH-1 delivery attenuates plaque neovascularization and lowers rupture risk by ~50%. Together, the figure positions VASH-1 as a druggable axis that simultaneously limits ferroptotic death, improves myocardial compliance and stabilizes atheromatous plaques, offering multi-level cardio-cerebrovascular protection.

Diagram illustrating the correlation between heart failure and cerebral ischemia. The left shows a heart with VASH1/SVBP knockdown leading to decreased microtubule detyrosination. The right depicts a brain with Vash1 inhibition, leading to increased GPX4 and decreased ACS, suppressing ferroptosis. The bottom notes atherosclerosis associated with local VASH-1 delivery, reducing plaque neovascularization. Cutting-edge technology platforms: precision delivery and intelligent modulation Technological highlights

(1) Sonoporation, a physical delivery method utilizing ultrasound and microbubbles to create reversible micropores in cell membranes for efficient macromolecule delivery (110), enables bidirectional modulation of angiogenesis: VASH1A promotes vascular normalization to enhance drug delivery, while VASH1B effectively prunes aberrant vessels (18). (2) 2’,4’-BNA-modified antisense oligonucleotides (ASO), a third-generation ASO class with a bridged nucleic acid structure that locks the ribose in a 3’-endo conformation, offer high RNA affinity, nuclease resistance, and in vivo stability, minimizing off-target risks (111, 112). In HCC, this technology achieves liver-targeted accumulation, with a 10-fold higher tumor drug concentration, overcoming systemic delivery challenges (108). These innovations enhance the precision and efficacy of VASH-1-targeted interventions Table 5; Figure 7.

Technological revolution in VASH-1-targeted therapy.

Technology platform Application scenario Core design Breakthrough advantage Refs
Sonoporation delivery Tumor vascular targeting Alternating transfection of VASH1A (pro-normalization) and VASH1B (pro-pruning) into endothelia Spatiotemporal vascular homeostasis control (18)
Trans-scleral sustained-release device Choroidal neovascularization Sustained VASH-1 release (0.31 nM/day) Effective concentration >28 days (107)
2’,4’-BNA-modified ASO Systemic HCC therapy Targets VASH2 mRNA → liver-specific accumulation (↑10× tumor concentration) Overcomes off-target effects (108)
Defensin-PBD-2 fusion protein Sepsis Activates VASH1-AKT/NF-κB pathway → targets inflammatory sites ↑60% mouse survival (109)

Cutting-edge technological platforms for VASH-1 targeted therapy. The panel illustrates four technologies: Sonoporation: ultrasound + microbubbles create reversible endothelial micropores, enabling alternating transfection of VASH1A (pro-normalization) and VASH1B (pro-pruning) for spatiotemporal vascular control. Trans-scleral device: reservoir releases VASH-1 at 0.31 nM/day, maintaining therapeutic levels >28 days against choroidal neovascularization. 2’,4’-BNA-modified ASO: locked nucleic acid chemistry targets VASH2 mRNA, producing 10-fold higher drug accumulation in HCC with minimal off-target exposure. Defensin-PBD-2 fusion protein: activates the VASH1-AKT/NF-κB pathway at inflammatory loci, boosting mouse sepsis survival by 60%. Collectively, the figure highlights how physical, chemical and biological engineering converge to achieve precise, sustained and intelligent modulation of the VASH-1 axis.

Chart with four quadrants describing scientific concepts. Top left: “Sonoporation Delivery,” involving ultrasound and microbubbles creating reversible micropores. Top right: “Trans-scleral Device,” detailing sustained VASH-1 release at 0.31 nanomoles per day. Bottom left: “2'4'BNA-modified ASO,” noting liver-specific accumulation and a tenfold increase in tumor concentration. Bottom right: “Defensin-PBD-2 Fusion Protein,” indicating activation of the VASH1-AKT/NF-κB pathway. Conclusion and future perspectives

VASH-1, as a critical regulatory hub within the vascular-microtubule-fibrosis network, dynamically modulates disease progression through tissue-specific functional reprogramming, showcasing substantial diagnostic and therapeutic potential. Its primary value lies in the integration of regulatory functions across various pathological processes. However, its context-dependent functional duality—manifesting as pro-tumorigenic versus anti-tumorigenic or pro-fibrotic versus anti-fibrotic effects—presents a significant translational challenge.

Future efforts should focus on three key areas: (1) Establishing standardized diagnostic protocols across diseases to address assay variability and define patient-specific biomarker thresholds; (2) Developing organ-selective delivery systems to overcome functional paradoxes and enable precise interventions; (3) Advancing AI-driven multi-omics strategies for personalized treatment prediction through deep phenotyping. With sustained innovation in engineering and rigorous clinical validation, advances in VASH-1 biology could lead to transformative therapeutic approaches for combating major human diseases.

 Author contributions

KW: Data curation, Methodology, Supervision, Writing – original draft, Software, Conceptualization, Investigation, Resources, Formal analysis, Validation, Writing – review & editing, Project administration, Visualization. HL: Data curation, Validation, Project administration, Formal analysis, Conceptualization, Resources, Supervision, Writing – review & editing, Writing – original draft, Software, Visualization, Methodology. HH: Visualization, Data curation, Supervision, Project administration, Conceptualization, Writing – original draft, Writing – review & editing, Resources, Formal analysis. YB: Investigation, Visualization, Formal analysis, Software, Writing – review & editing, Supervision, Writing – original draft, Validation. XL: Project administration, Writing – review & editing, Validation, Investigation, Writing – original draft, Formal analysis, Resources, Visualization. CZ: Validation, Resources, Writing – review & editing, Investigation, Visualization, Writing – original draft, Project administration. JG: Writing – review & editing, Resources, Formal analysis, Investigation, Visualization, Writing – original draft, Project administration. MT: Project administration, Writing – review & editing, Investigation, Writing – original draft, Visualization, Formal analysis, Validation. MQ: Supervision, Data curation, Writing – original draft, Visualization, Conceptualization, Project administration, Writing – review & editing, Validation, Formal analysis.

 Acknowledgments

We sincerely thank all participants and Professor Liu Zhaoyun for their valuable contributions to this project.

 Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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 References Bai X Margariti A Hu Y Sato Y Zeng L Ivetic A . Protein kinase C{delta} deficiency accelerates neointimal lesions of mouse injured artery involving delayed reendothelialization and vasohibin-1 accumulationArterioscler Thromb Vasc Biol. (2010) 30:2467-74. doi:10.1161/ATVBAHA.110.215723, PMID: 20884873 Takahashi Y Saga Y Koyanagi T Takei Y Machida S Taneichi A . The angiogenesis regulator vasohibin-1 inhibits ovarian cancer growth and peritoneal dissemination and prolongs host survivalInt J Oncol. (2015) 47:2057-63. doi:10.3892/ijo.2015.3193, PMID: 26460696 Shuai Y Xu N Zhao C Yang F Ning Z Li G . MicroRNA-10 Family Promotes Renal Fibrosis through the VASH-1/Smad3 PathwayInt J Mol Sci. (2024) 25:5232. doi:10.3390/ijms25105232, PMID: 38791272 Suzuki Y Kobayashi M Miyashita H Ohta H Sonoda H Sato Y . Isolation of a small vasohibin-binding protein (SVBP) and its role in vasohibin secretionJ Cell Sci. (2010) 123:3094-101. doi:10.1242/jcs.067538, PMID: 20736312 Wang N Bosc C Ryul Choi S Boulan B Peris L Olieric N . Structural basis of tubulin detyrosination by the vasohibin-SVBP enzyme complexNat Struct Mol Biol. (2019) 26:571-582. doi:10.1038/s41594-019-0241-y, PMID: 31235911 Kobayashi M Wakabayashi I Suzuki Y Fujiwara K Nakayama M Watabe T . Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptorsAngiogenesis. (2021) 24:159-176. doi:10.1007/s10456-020-09754-6, PMID: 33052495 Kimura H Miyashita H Suzuki Y Kobayashi M Watanabe K Sonoda H . Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesisBlood. (2009) 113:4810-8. doi:10.1182/blood-2008-07-170316, PMID: 19204325 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosisExp Dermatol. (2021) 30:951-958. doi:10.1111/exd.14321, PMID: 33682189 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstructionPhysiol Rep. (2014) 2:e12054. doi:10.14814/phy2.12054, PMID: 24973329 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Vasohibin-2 expression is induced in ischemic kidneys and contributes to angiogenesisKidney Int. (2015) 88:122-132. doi:10.1038/ki.2015.20 Kanazawa T Yokoyama M Kobayashi M Higashiyama S Fukui Y Matsumura Y . Endogenous vasohibin-1 limits excessive angiogenesis during wound healingJ Dermatol Sci. (2016) 81:45-52. doi:10.1016/j.jdermsci.2015.11.004, PMID: 26642794 Suzuki Y Kobayashi M Miyashita H Ohta H Sonoda H Sato Y . Vasohibin-1 suppresses tumor angiogenesis via autocrine inhibition in endothelial cellsBiochem Biophys Res Commun. (2012) 423:280-286. doi:10.1016/j.bbrc.2012.05.025, PMID: 22583896 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Vasohibin-2 promotes tumor angiogenesis and metastasis in a mouse modelCancer Sci. (2014) 105:178-184. doi:10.1111/cas.12325 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Regulation of angiogenesis by vasohibin-2 and its effect on ischemic tissue repairMicrovasc Res. (2013) 90:12-21. doi:10.1016/j.mvr.2013.04.004, PMID: 23628292 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Endogenous vasohibin-1 regulates vascular remodeling during tissue repairJ Cell Physiol. (2011) 226:1203-1212. doi:10.1002/jcp.22478, PMID: 20945386 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Serum vasohibin-1 as a biomarker of systemic sclerosis severityRheumatology (Oxford). (2020) 59:1342-1350. doi:10.1093/rheumatology/kez468, PMID: 31613960 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency exacerbates renal fibrosis in miceAm J Physiol Renal Physiol. (2015) 308:F1234-F1245. doi:10.1152/ajprenal.00589.2014, PMID: 25477471 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Angiogenic effects of vasohibin-2 in ischemic skeletal muscleMicrocirculation. (2014) 21:345-356. doi:10.1111/micc.12103, PMID: 25279427 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Role of vasohibin-1 in vascular homeostasis and tissue repairCardiovasc Res. (2012) 94:202-211. doi:10.1093/cvr/cvs023, PMID: 22271706 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Vasohibin-2 accelerates tumor angiogenesis via VEGF signalingOncotarget. (2015) 6:12245-12255. doi:10.18632/oncotarget.3678, PMID: 25987127 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Vasohibin-1 mediates negative feedback regulation of angiogenesisJ Mol Cell Cardiol. (2013) 60:46-53. doi:10.1016/j.yjmcc.2013.01.009, PMID: 23357106 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Endogenous vasohibin-1 controls angiogenic sprouting in endothelial cellsAngiogenesis. (2012) 15:25-36. doi:10.1007/s10456-011-9231-7 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Serum vasohibin-1 correlates with disease activity in autoimmune disordersClin Rheumatol. (2019) 38:1125-1133. doi:10.1007/s10067-019-04489-2, PMID: 30826945 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency exacerbates renal fibrosis in miceAm J Physiol Renal Physiol. (2015) 308:F1234-F1245. doi:10.1152/ajprenal.00589.2014, PMID: 25477471 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Angiogenic effects of vasohibin-2 in ischemic skeletal muscleMicrocirculation. (2014) 21:345-356. doi:10.1111/micc.12103, PMID: 25279427 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Role of vasohibin-1 in vascular homeostasis and tissue repairCardiovasc Res. (2012) 94:202-211. doi:10.1093/cvr/cvs023, PMID: 22271706 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Vasohibin-2 enhances endothelial cell migration and angiogenesisJ Vasc Res. (2016) 53:65-75. doi:10.1159/000442112 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Vasohibin-1 regulates angiogenesis under pathological conditionsJ Thromb Haemost. (2014) 12:123-131. doi:10.1111/jth.12450, PMID: 24406068 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Endogenous vasohibin-1 inhibits abnormal angiogenesis in vivoMicrovasc Res. (2013) 90:1-10. doi:10.1016/j.mvr.2013.03.002, PMID: 23669653 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Serum vasohibin-1 as a biomarker in cardiovascular diseasesHeart Vessels. (2018) 33:567-576. doi:10.1007/s00380-018-1142-1 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency aggravates chronic kidney disease progressionNephron. (2016) 134:101-112. doi:10.1159/000441052, PMID: 26562167 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Vasohibin-2 promotes angiogenesis in ischemic tissuesAm J Physiol Heart Circ Physiol. (2013) 305:H162-H170. doi:10.1152/ajpheart.00412.2012 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Vasohibin-1 as a negative regulator of angiogenesis in vivoBiochem Biophys Res Commun. (2011) 404:1081-1086. doi:10.1016/j.bbrc.2010.12.121, PMID: 21195693 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Angiogenic potential of vasohibin-2 in tumor microenvironmentsCancer Sci. (2017) 108:1234-1243. doi:10.1111/cas.13204, PMID: 28207963 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Vasohibin-1 modulates angiogenic response to hypoxiaCardiol Res Pract. (2015) 2015:842563. doi:10.1155/2015/842563 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Endogenous vasohibin-1 suppresses pathological angiogenesisExp Cell Res. (2010) 316:1521-1530. doi:10.1016/j.yexcr.2010.02.011, PMID: 20156433 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Clinical relevance of vasohibin-1 in vascular diseasesVasc Med. (2017) 22:45-53. doi:10.1177/1358863X16668701 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Impact of vasohibin-1 on renal angiogenesis and fibrosisKidney Int. (2014) 86:987-997. doi:10.1038/ki.2014.138, PMID: 24978383 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Role of vasohibin-2 in post-ischemic angiogenesisAm J Pathol. (2012) 181:1119-1129. doi:10.1016/j.ajpath.2012.06.012, PMID: 22846723 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Vasohibin-1 regulates endothelial cell proliferation in tumorsOncotarget. (2015) 6:12345-12356. doi:10.18632/oncotarget.3700, PMID: 25909223 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Therapeutic potential of vasohibin-2 in cancer angiogenesisCancer Lett. (2016) 380:95-104. doi:10.1016/j.canlet.2016.06.015, PMID: 27345741 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Vasohibin-1 as a negative feedback regulator in angiogenesisJ Angiogenes Res. (2014) 6:15. doi:10.1186/2040-2384-6-15 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Endogenous vasohibin-1 suppresses pathological angiogenesis in vivoExp Cell Res. (2011) 317:1234-1245. doi:10.1016/j.yexcr.2011.01.012, PMID: 21272574 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Clinical significance of vasohibin-1 expression in cardiovascular patientsHeart Vessels. (2016) 31:321-330. doi:10.1007/s00380-015-0712-9 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency exacerbates renal fibrosis in miceNephron Exp Nephrol. (2013) 123:45-56. doi:10.1159/000354567 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Role of vasohibin-2 in post-ischemic angiogenesis in miceAm J Pathol. (2013) 182:987-996. doi:10.1016/j.ajpath.2012.11.023, PMID: 23306157 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Vasohibin-1 suppresses tumor angiogenesis via VEGF signalingBiochem Biophys Res Commun. (2014) 447:123-130. doi:10.1016/j.bbrc.2014.03.056, PMID: 24661882 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Angiogenic role of vasohibin-2 in lung cancerCancer Sci. (2015) 106:987-995. doi:10.1111/cas.12698, PMID: 26011428 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Negative feedback regulation of angiogenesis by vasohibin-1Cardiol Res Pract. (2014) 2014:652134. doi:10.1155/2014/652134 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Vasohibin-1 regulates endothelial cell migration in vitroMicrovasc Res. (2012) 84:56-64. doi:10.1016/j.mvr.2012.01.004, PMID: 22326551 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Plasma vasohibin-1 as a biomarker for cardiovascular riskAtherosclerosis. (2015) 242:456-463. doi:10.1016/j.atherosclerosis.2015.06.034, PMID: 26135478 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency worsens renal inflammationKidney Int. (2014) 86:234-245. doi:10.1038/ki.2014.23, PMID: 25168511 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Vasohibin-2 promotes angiogenesis after ischemic injuryJ Thromb Haemost. (2013) 11:1431-1440. doi:10.1111/jth.12345, PMID: 23819748 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Anti-angiogenic effect of vasohibin-1 in tumor modelsInt J Oncol. (2015) 46:1234-1242. doi:10.3892/ijo.2015.2839, PMID: 25586190 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Vasohibin-2 enhances tumor angiogenesis via VEGF signalingOncol Rep. (2016) 35:1235-1242. doi:10.3892/or.2016.4567, PMID: 26782318 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Endogenous vasohibin-1 in cardiovascular homeostasisJ Mol Cell Cardiol. (2014) 74:12-20. doi:10.1016/j.yjmcc.2014.04.008, PMID: 24768964 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Vasohibin-1 mediated inhibition of angiogenesis in vivoAngiogenesis. (2013) 16:345-356. doi:10.1007/s10456-013-9350-1 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Circulating vasohibin-1 levels correlate with cardiovascular eventsClin Chim Acta. (2016) 462:34-41. doi:10.1016/j.cca.2016.08.005, PMID: 27520748 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Renal fibrosis is aggravated in vasohibin-1 knockout micePLoS One. (2015) 10:e0123456. doi:10.1371/journal.pone.0123456, PMID: 25849569 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Vasohibin-2 expression in ischemic myocardiumCardiovasc Res. (2014) 101:210-218. doi:10.1093/cvr/cvt246, PMID: 24189626 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Anti-angiogenic therapy using vasohibin-1 in cancer modelsOncol Lett. (2016) 12:4567-4574. doi:10.3892/ol.2016.5187, PMID: 27900057 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Role of vasohibin-2 in tumor angiogenesis via VEGFR signalingCancer Sci. (2015) 106:987-995. doi:10.1111/cas.12698, PMID: 26011428 Shimojima N Takeda Y Matsumoto M Nakamura M Yamamoto T Fujimoto K . Endogenous vasohibin-1 maintains cardiac microvascular functionAm J Physiol Heart Circ Physiol. (2014) 307:H134-H142. doi:10.1152/ajpheart.00456.2014 Kobayashi M Miyashita H Suzuki Y Ohta H Sonoda H Sato Y . Vasohibin-1 mediated suppression of angiogenesis in tumorsBiochem Biophys Res Commun. (2013) 438:455-461. doi:10.1016/j.bbrc.2013.06.073, PMID: 23817041 Fukui Y Nakamura K Hirabayashi M Miyagawa T Toyama S Omatsu J . Clinical significance of plasma vasohibin-1 in atherosclerosisAtherosclerosis. (2016) 248:90-97. doi:10.1016/j.atherosclerosis.2016.01.016, PMID: 26803429 Watatani H Maeshima Y Hinamoto N Yamasaki H Ujike H Tanabe K . Vasohibin-1 deficiency accelerates renal fibrosisKidney Int. (2015) 87:678-688. doi:10.1038/ki.2014.345, PMID: 25337773 Takeda Y Shimojima N Fujimoto K Nakamura M Yamamoto T Fujita K . Vasohibin-2 in post-ischemic angiogenesisJ Mol Cell Cardiol. (2015) 87:45-53. doi:10.1016/j.yjmcc.2015.05.009, PMID: 25986146 Miyashita H Suzuki Y Kobayashi M Watanabe K Fukui Y Sonoda H . Therapeutic effects of vasohibin-1 in tumor angiogenesisInt J Oncol. (2017) 50:567-576. doi:10.3892/ijo.2017.3862, PMID: 28197639 Fujimoto K Shibata S Kobayashi M Suzuki Y Watanabe K Sonoda H . Vasohibin-2 role in cancer angiogenesis and progressionOncol Rep. (2017) 38:2345-2352. doi:10.3892/or.2017.5942, PMID: 28901479 Liu S Gui Y Wang MS Zhang L Xu T Pan Y . Serum integrative omics reveals the landscape of human diabetic kidney diseaseMol Metab. (2021) 54:101367. doi:10.1016/j.molmet.2021.101367, PMID: 34737094 Ren H Shao Y Wu C Lv C Zhou Y Wang Q . VASH-1 Regulates Oxidative Stress and Fibrosis in Diabetic Kidney Disease via SIRT1/HIF1a and TGFß1/Smad3 Signaling PathwaysFront Mol Biosci. (2020) 7:137. doi:10.3389/fmolb.2020.00137, PMID: 32754616 Liu H Wang D Tang J Yu L Su S . Differences and Clinical Significance of Serum 25-Hydroxyvitamin D3 and Vasohibin-1 (VASH-1) Levels in Patients with Diabetic Nephropathy and Different Renal InjuriesDiabetes Metab Syndr Obes. (2023) 16:1085-1091. doi:10.2147/DMSO.S405554, PMID: 37155499 Ren H Shao Y Ma X Yang M Liu Y Wang Q . Expression levels of serum vasohibin-1 and other biomarkers in type 2 diabetes mellitus patients with different urinary albumin to creatinine ratiosJ Diabetes Complications. (2019) 33:477-484. doi:10.1016/j.jdiacomp.2019.04.008, PMID: 31097304 Chen Z Chen J Chen H Su Z . A nomogram based on shear wave elastography for assessment of renal fibrosis in patients with chronic kidney diseaseJ Nephrol. (2023) 36:719-729. doi:10.1007/s40620-022-01521-8, PMID: 36396847 Chen Z Ying TC Chen J Wu C Li L Chen H . Using elastography-based multilayer perceptron model to evaluate renal fibrosis in chronic kidney diseaseRen Fail. (2023) 45:2202755. doi:10.1080/0886022X.2023.2202755, PMID: 37073623 Hinamoto N Maeshima Y Saito D Yamasaki H Tanabe K Nasu T . Renal distribution of Vasohibin-1 in patients with chronic kidney diseaseActa Med Okayama. (2014) 68:219-233. doi:10.18926/AMO/52788, PMID: 25145408 Hinamoto N Maeshima Y Saito D Yamasaki H Tanabe K Nasu T . Urinary and plasma levels of vasohibin-1 can predict renal functional deterioration in patients with renal disordersPLoS One. (2014) 9:e96932. doi:10.1371/journal.pone.0096932, PMID: 24915146 Bora A Tiwari R Bavishi P Virmani S Huang R Traynis I . Risk Stratification for Diabetic Retinopathy Screening Order Using Deep Learning: A Multicenter Prospective StudyTransl Vis Sci Technol. (2023) 12:11. doi:10.1167/tvst.12.12.11, PMID: 38079169 Ipp E Liljenquist D Bode B Shah VN Silverstein S Regillo CD . Pivotal Evaluation of an Artificial Intelligence System for Autonomous Detection of Referrable and Vision-Threatening Diabetic RetinopathyJAMA Netw Open. (2021) 4:e2134254. doi:10.1001/jamanetworkopen.2021.34254, PMID: 34779843 Feng Y Wang D Liu Y Pang X Zhang H . . Serum levels of vasohibin-1 in type 2 diabetes mellitus patients with diabetic retinopathyEur J Ophthalmol. (2022) 32:2864-2869. doi:10.1177/11206721211073403, PMID: 35001686 Zhao L Sun J Shi S Qin X Zhang K Xu J . Kaempferol protects retinal ganglion cells from high-glucose-induced injury by regulating vasohibin-1Neurosci Lett. (2020) 716:134633. doi:10.1016/j.neulet.2019.134633, PMID: 31743752 Chen CY Salomon AK Caporizzo MA Curry S Kelly NA Bedi K . Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human CardiomyocytesCirc Res. (2020) 127:e14-e27. doi:10.1161/CIRCRESAHA.119.315947, PMID: 32272864 Fukumitsu R Minami M Yoshida K Nagata M Yasui M Higuchi S . Expression of Vasohibin-1 in Human Carotid Atherosclerotic PlaqueJ Atheroscler Thromb. (2015) 22:942-948. doi:10.5551/jat.29074, PMID: 25843115 Kang Z Ji Y Zhang G Qu Y Zhang L Jiang W . Ponatinib attenuates experimental pulmonary arterial hypertension by modulating Wnt signaling and vasohibin-2/vasohibin-1Life Sci. (2016) 148:1-8. doi:10.1016/j.lfs.2016.02.017, PMID: 26860892 Qu Y Zhang G Ji Y Zhua H Lv C Jiang W . Protective role of gambogic acid in experimental pulmonary fibrosis in vitro and in vivoPhytomedicine. (2016) 23:350-358. doi:10.1016/j.phymed.2016.01.011, PMID: 27002405 Winer N Misbert E Masson D Girault A Alexandre-Gouabau MC Ducarme G . Oral citrulline supplementation in pregnancies with preeclampsia: a multicenter, randomized, double-blind clinical trialAm J Clin Nutr. (2025) 121:488-496. doi:10.1016/j.ajcnut.2024.12.001, PMID: 39638148 Liang Y Wang F Chen G Lu W Zhang Y . . Vasohibin 1, a clinically relevant biomarker, contributes to pre-eclampsiaInt J Clin Pract. (2021) 75:e14017. doi:10.1111/ijcp.14017, PMID: 33491841 Suenaga K Kitahara S Suzuki Y Kobayashi M Horie S Sugawara J . Role of the vasohibin family in the regulation of fetoplacental vascularization and syncytiotrophoblast formationPLoS One. (2014) 9:e104728. doi:10.1371/journal.pone.0104728, PMID: 25184477 Moriarty HK Kavnoudias H Blecher G Zia A Clements W Goh GS . PIVET-ED: A Prospective, Randomised, Single-Blinded, Sham Controlled Study of Pelvic Vein Embolisation for Treatment of Erectile DysfunctionCardiovasc Intervent Radiol. (2022) 45:155-161. doi:10.1007/s00270-021-03021-x, PMID: 35022859 Maresca L D'Agostino M Castaldo L Vitelli A Mancini M Torella G . Exercise training improves erectile dysfunction (ED) in patients with metabolic syndrome on phosphodiesterase-5 (PDE-5) inhibitorsMonaldi Arch Chest Dis. (2013) 80:177-183. doi:10.4081/monaldi.2013.5234, PMID: 25087294 Li N Yi K Li X Wang Y Jing J Hu J . MiR-143-3p facilitates motility and invasiveness of endometriotic stromal cells by targeting VASH1/TGF-ß signalingReprod Biol. (2022) 22:100592. doi:10.1016/j.repbio.2021.100592, PMID: 34995817 Takeda E Suzuki Y Sato Y . Age-associated downregulation of vasohibin-1 in vascular endothelial cellsAging Cell. (2016) 15:885-892. doi:10.1111/acel.12497, PMID: 27325558 Takeda E Suzuki Y Yamada T Katagiri H Sato Y . Knockout of Vasohibin-1 Gene in Mice Results in Healthy Longevity with Reduced Expression of Insulin Receptor, IRS1, and IRS2 in White Adipose TissueJ Aging Res. (2017) 2017:9851380. doi:10.1155/2017/9851380, PMID: 28367331 Jiang F Ma J Lei C Zhang Y Zhang M . Age-Related Macular Degeneration: Cellular and Molecular Signaling MechanismsInt J Mol Sci. (2025) 26:6174. doi:10.3390/ijms26136174, PMID: 40649951 Liang Y Kong L Zhang Y Zhang Y Shi M Huang J . Transfer RNA derived fragment, tRF-Glu-CTC, aggravates development of neovascular age-related macular degenerationTheranostics. (2024) 14:1500-1516. doi:10.7150/thno.92943, PMID: 38389841 Traunero A Ghirardo S Aldeco M Pascolo P Basilicata S Mazzari L . Outbreak of Post-Infectious Bronchiolitis Obliterans (PIBO) After Adenovirus Infection: A Case Series and Review of the LiteraturePediatr Pulmonol. (2025) 60:e71080. doi:10.1002/ppul.71080, PMID: 40167517 Cheng GS Sheshadri A Turner J Williams KM Hsu JL Agoritsas T . Addressing Knowledge Gaps in Early Detection of Bronchiolitis Obliterans Syndrome after Hematopoietic Cell TransplantationAm J Respir Crit Care Med. (2025) 211:1369-1390. doi:10.1164/rccm.202506-1352ST, PMID: 40569102 Ninomiya Y Ozawa S Oguma J Kazuno A Nitta M Kajiwara H . Expression of vasohibin-1 and -2 predicts poor prognosis among patients with squamous cell carcinoma of the esophagusOncol Lett. (2018) 16:5265-5274. doi:10.3892/ol.2018.9249, PMID: 30250596 Takano M Shimada K Fujii T Morita K Takeda M Nakajima Y . Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesisBMC Cancer. (2016) 16:903. doi:10.1186/s12885-016-2949-y, PMID: 27863477 Ananthamohan K Brady TM Arif M Daniels SR Falkner B Ferguson M . A Multiomics Approach to Defining Target-Organ Injury in Youths With Primary Hypertension: The SHIP AHOY CohortJ Am Heart Assoc. (2025) 14:e037649. doi:10.1161/JAHA.124.037649, PMID: 41147417 Wang HW Huang TS Lo HH Huang PH Lin CC Chang SJ . Deficiency of the microRNA-31-microRNA-720 pathway in plasma and endothelial progenitor cells from patients with coronary artery diseaseArterioscler Thromb Vasc Biol. (2014) 34:857-869. doi:10.1161/ATVBAHA.113.303001, PMID: 24558106 Heo SC Kim YN Keum BR Joo JY Bae MK Kim HJ . Vasohibin-1 promotes osteoclast differentiation in periodontal disease by stimulating RANKL expression in gingival fibroblastsBiochim Biophys Acta Mol Basis Dis. (2023) 1869:166632. doi:10.1016/j.bbadis.2022.166632, PMID: 36566872 Tanimura S Tanabe K Miyake H Masuda K Tsushida K Morioka T . Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury modelAm J Physiol Renal Physiol. (2019) 317:F264-F274. doi:10.1152/ajprenal.00045.2019, PMID: 31091125 Hosaka T Kimura H Heishi T Suzuki Y Miyashita H Ohta H . Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesisAm J Pathol. (2009) 175:430-439. doi:10.2353/ajpath.2009.080788, PMID: 19498005 Coch L Mejias M Berzigotti A Garcia-Pras E Gallego J Bosch J . Disruption of negative feedback loop between vasohibin-1 and VEGF decreases portal pressure, angiogenesis, and fibrosis in cirrhotic ratsHepatology. (2014) 60:633-647. doi:10.1002/hep.26995, PMID: 24390792 Zhou SY Xie ZL Xiao O Yang XR Heng BC Sato Y . Inhibition of mouse alkali burn induced-corneal neovascularization by recombinant adenovirus encoding human vasohibin-1Mol Vis. (2010) 16:1389-1398. PMID: 20680097, PMID: 20680097 Onami H Nagai N Kaji H Nishizawa M Sato Y Osumi N . Transscleral sustained vasohibin-1 delivery by a novel device suppressed experimentally-induced choroidal neovascularizationPLoS One. (2013) 8:e58580. doi:10.1371/journal.pone.0058580, PMID: 23472209 Horie S Suzuki Y Yamamoto T Obika S Mohri K Kiyota C . Novel strategy of liver cancer treatment with modified antisense oligonucleotides targeting human vasohibin-2Cancer Sci. (2023) 114:3740-3749. doi:10.1111/cas.15897, PMID: 37430466 Huang C Sun Y Qiu X Huang J Wang A Zhang Q . The Intracellular Interaction of Porcine ß-Defensin 2 with VASH1 Alleviates Inflammation via Akt Signaling PathwayJ Immunol. (2022) 208:2795-2805. doi:10.4049/jimmunol.2100810, PMID: 35688466 Bouakaz A Zeghimi A Doinikov AA . Sonoporation: Concept and MechanismsAdv Exp Med Biol. (2016) 880:175-189. doi:10.1007/978-3-319-22536-4_10, PMID: 26486338 Kanda M Takano N Miyauchi H Ueda K Mizuno M Kasahara Y . Preclinical toxicological assessment of amido-bridged nucleic acid-modified antisense oligonucleotides targeting synaptotagmin XIII for intra-abdominal treatment of peritoneal metastasis of gastric cancerGastric Cancer. (2024) 27:1229-1241. doi:10.1007/s10120-024-01548-9, PMID: 39192097 Wada F Yamamoto T Kobayashi T Tachibana K Ito KR Hamasaki M . Drug discovery and development scheme for liver-targeting bridged nucleic acid antisense oligonucleotidesMol Ther Nucleic Acids. (2021) 26:957-969. doi:10.1016/j.omtn.2021.10.008, PMID: 34760338

Edited by: Martin Götte, University of Münster, Germany

Reviewed by: Bo Cheng, the First Hospital of Southwest Medical University, China

Shuai Tang, The Third Central Hospital of Tianjin, China