Increasing evidence suggests that local tissues, which were previously thought to be passive recipients of immunity, have equally active regulatory functions (Galli et al., 2011). The requirements of the tissues to which immune cells are recruited or reside are constantly changing, and the function of these cells is constantly being adapted (Galli et al., 2011; Matzinger and Kamala, 2011; Oyler-Yaniv et al., 2017). Immune plasticity can manifest at different levels, from the cellular to the molecular level (Galli et al., 2011). Cellular plasticity refers to the ability of cells to adapt and change their characteristics or functions in response to various stimuli or environmental cues (Oyler-Yaniv et al., 2017; Hajishengallis and Chavakis, 2019).

DEL-1 is a 52 kDa protein encoded by the EDIL3 gene (C Hidai 1, 1998). DEL-1 contains three epidermal growth factor (EGF)-like repeats at the N-terminus and the Arg-Gly-Asp (arginine-glycine-aspartate, RGD) module in the second EGF domain (EGF2) which combines with integrin to form a recognition system for cell adhesion (Ruoslahti, 1996; Schurpf et al., 2012). At the C-terminus, DEL-1 has two discoidal I-like domains capable of glycosaminoglycan and phosphatidylserine interactions (Hanayama et al., 2004; Hidai et al., 2007). DEL-1 is released from endothelial cells, mesenchymal stromal cells, and subsets of macrophages (Hajishengallis and Chavakis, 2019). DEL-1, due to its unique structure, can interact with a variety of integrin types, including Macrophage-1 antigen (Mac-1, αMβ2 integrin), lymphocyte function-associated antigen 1 (LFA-1, αLβ2 integrin), αvβ3 integrin, αvβ6 integrin (Choi, 2009; Mitroulis et al., 2014; Kim et al., 2020; Li et al., 2021a). Its presence suggests that local factors regulate immune plasticity within tissues to maintain or reinstate tissue homeostasis (see Figure 1).

DEL-1 may promote atherosclerosis, contrary to earlier descriptions of its anti-inflammatory and efferocytosis effects (Hajishengallis and Chavakis, 2019). Surprisingly, DEL-1 expression was predominantly localized to foam cells within the intimal layers of coronary arteries in patients with coronary heart disease (CHD) and sudden cardiac death (SCD) and was significantly elevated compared to that in healthy people. In ApoE^-/- mice, a positive correlation was observed between macrophage-derived DEL-1 levels and various atherosclerosis-related factors, such as plaque area, luminal stenosis, plaque foam cell counts, and downstream inflammatory factors. Moreover, the inhibition of the upstream pathway resulted in the suppression of DEL-1 expression, thereby exacerbating atherosclerotic lesions (Lu et al., 2023). This finding underscores the potential significance of DEL-1 in the regulation of atherosclerosis and warrants further investigation of its role in atherosclerosis. Previous studies have indicated that DEL-1 inhibits the production of macrophage migration inhibitor (MIF) in macrophages and also suppresses nuclear factor kappa-B (NF-κB)-mediated downstream inflammatory activation. DEL-1 is implicated in cardiovascular pathology through contrasting roles; while it appears to confer protection against inflammatory processes and vascular damage, recent evidence shows it may be associated with the promotion of atherosclerosis (Lee et al., 2014).

Chronic local inflammatory dysregulation may disrupt the regulation of endothelial immunity, such as enhanced vascular permeability, which regulates the recruitment of white blood cells and the activation of immune cells, may be impaired (Lee et al., 2014; Wang et al., 2022a). Instead, macrophages exert their pro-inflammatory effects after foam cell formation during atherosclerosis (Rader and Puré, 2005; Li et al., 2022a). The study mentioned above did not investigate the effects of the specific regulation of DEL-1 on downstream signaling, and there may be non-redundant signals other than DEL-1 that play a cross-regulatory role, thus affecting the results. However, previous research has shown that DEL-1 can bind to the phospholipid structure of oxidized low-density lipoprotein (oxLDL) and can inhibit the uptake of oxLDL by human coronary artery endothelial cells (HCAECs) or macrophages in a dose-dependent manner (Kakino et al., 2016). DEL-1 also inhibits the oxLDL-induced expression of monocyte chemoattractant protein-1 (MCP-1) and ICAM-1, as well as the secretion of endothelin-1 by HCAECs, ultimately mitigating atherosclerosis (Bennett et al., 2016; Kakino et al., 2016). The impact of the mice’s age on the experimental results has not yet been determined. There are methodological differences between the use of different drugs in animal models of atherosclerosis that may contribute to discrepancies in research findings related to the role of DEL-1 in atherosclerosis (Kakino et al., 2016; Emini Veseli et al., 2017). Given the variance in findings, it is critical to verify the physiological role of DEL-1 in atherosclerosis using a variety of animal models to ensure the consistency and reproducibility of results.

Additionally, overexpression of DEL-1 under atherosclerotic conditions may only be a feed-forward mechanism closely related to the complex inflammatory state of the disease and is not sufficient to suggest that DEL-1 promotes atherosclerosis (Di Pietro et al., 2023). DEL-1 effectively regulates the recruitment and chemotaxis of leukocytes, thereby preventing excessive inflammation (Hajishengallis and Chavakis, 2019). This is an important mechanism of its potential therapeutic effect.

Angiogenesis, the process of forming new blood vessels, is driven by signals originating from surrounding tissues (Ramasamy et al., 2015; Jeong et al., 2021). Endothelial cells not only participate in this process by releasing proangiogenic growth factors but also exhibit dramatic plasticity, regulating vascular shape and organization through autocrine and paracrine signaling mechanisms (Bentley et al., 2014; McCoy et al., 2021). They can release inflammatory mediators, cell adhesion molecules, and immunomodulatory molecules to regulate normal vascular physiology (Shao et al., 2020). When endothelial cells are exposed to pathogens or inflammatory stressors, they may undergo a cascade of maladaptive changes including disruption of glycolytic and lipoprotein pathways, thereby contributing to vascular diseases (Xu et al., 2021).

DEL-1 is notable for its role in promoting angiogenesis, which is the formation of new blood vessels. The protein is actively expressed by embryonic endothelial cells where it contributes to the intricate shaping and remodeling of the developing vasculature, illustrating its importance during early growth stages (Hidai et al., 1998). DEL-1-induced angiogenesis is dependent on the integrins αvβ3 and αvβ5, in addition to some forms of embryonic and tumor-induced angiogenesis (Zhong et al., 2003). Studies have demonstrated that DEL-1 can interact with vascular endothelial growth factor (VEGF) to regulate its role in angiogenesis (Zou et al., 2009; Niu et al., 2023). This interaction may have the potential to prevent aortic dissection by increasing VEGF pathway inhibitors (Oshima et al., 2017).

Evidence suggests that DEL-1 (whether administered or overexpressed) contributes to angiogenesis, and a lack of endogenous DEL-1 has not been shown to impact normal angiogenesis in animal models (Ho et al., 2004). The aortic ring assay showed that neither endothelial angiogenesis nor developmental angiogenesis in the retina was affected by DEL-1 deficiency (Klotzsche-von Ameln et al., 2017). This suggests that constitutive DEL-1 expression does not promote physiological angiogenesis (Hsu et al., 2008). It has been suggested that DEL-1 prevents ischemia-driven neovascularization by inhibiting inflammatory activation downstream of αLβ2 (Klotzsche-von Ameln et al., 2017). The functional differences exhibited by DEL-1, may be influenced by environmental factors. In the disc angiogenesis system, DEL-1 was shown to upregulate the expression of fibroblast growth factor and significantly enhance fibrovascular growth (Ho et al., 2004). Clinical investigations into DEL-1’s therapeutic applications have shown promise, with the administration of DEL-1 plasmids leading to improved clinical manifestations in patients suffering from peripheral arterial disease, though the improvements did not achieve statistical significance, which warrants further study to conclusively determine efficacy (Grossman et al., 2007).

An increase in endothelial expression of DEL-1 can promote angiogenesis and endothelial cell migration (Beckham et al., 2014; Cobb et al., 2021). Cohort studies of patients with uterine cancer have shown that an increase in EDIL3 in dermal mesenchymal stem cells (DMSCs) stimulates the expression of αvβ3 and α5β1 from endothelial cells and promotes endothelium-associated angiogenesis (Niu et al., 2022a; Niu et al., 2022b). These changes were not limited to physiological conditions. DEL-1 expression levels in psoriatic DMSCs are 2.54-fold higher than those in healthy controls (Niu et al., 2016). This activation results in excessive angiogenesis and vasodilation, ultimately leading to an increase in both epidermal thickness and microvascular density (Niu et al., 2020; Niu et al., 2022b). DEL-1 can promote vascular repair and neovascularization, leading to adverse remodeling. DEL-1 also interacts with αvβ6 integrin, which is a known activator of transforming growth factor-beta (TGF-β), and effectively inhibits integrin-mediated TGF-β activation. Interestingly, the DEL-1-mediated inhibition of TGF-β signaling only occurs in response to increased levels of αv integrins (Kim et al., 2020). Specifically, DEL-1 mediates the activation of TGF-β and ERK signaling, promoting epithelial-mesenchymal transition (EMT) and angiogenesis, a critical step that can contribute to the distant metastasis of tumor cells in hepatocellular carcinoma (Xia et al., 2015; Jeong et al., 2017).

The angiogenic effects of DEL-1 promote distant metastasis of tumor cells. However, DEL-1 inhibits inflammatory cell migration, thereby reducing associated tumor complications (Hyun et al., 2020). Further molecular and clinical research is crucial to determine the potential role of DEL-1 in the pathophysiology and treatment of peripheral vascular disease. It is also important to investigate whether uncontrolled neovascularisation and adverse vascular remodeling might occur.

Serving as versatile effectors in both thrombosis and hemostasis, platelets orchestrate immune responses by releasing pro-inflammatory cytokines, including IL-1β, thereby enhancing endothelial permeability and guiding other immune cells to areas of injury or infection (Pober and Sessa, 2007; Koupenova et al., 2018; Margraf and Zarbock, 2019).

Platelet microparticles (PMPs) are tiny fragments of cells that are released from platelets, which can be triggered by different stimuli, such as the activation of platelets by thrombin, collagen, or other agonists. Platelet overactivation and PMPs play a key role in the pathogenesis of cardiovascular and autoimmune diseases (Lannan et al., 2014). The size of PMPs depends on the nature of cell activation stimuli (Ponomareva et al., 2017).

The adhesion of platelets to the activated endothelium is facilitated by increased expression of adhesion molecules. This process, along with the subsequent binding of platelets to leukocytes, is crucial for forming platelet-leukocyte aggregates. These aggregates are instrumental in atherogenesis, with ongoing platelet-leukocyte interactions being a central component of this pathology (May et al., 2007; Twarock et al., 2016; Pircher et al., 2019). In a high-glucose environment, PMPs markedly diminish endothelial nitric oxide (NO) bioavailability while concurrently amplifying reactive oxygen species (ROS) synthesis. This dual action exacerbates endothelial dysfunction, culminating in heightened permeability and cellular damage (Wang et al., 2019a).

DEL-1 binds to platelet phosphatidylserine and mediates endothelial clearance of platelet particles. Due to redundant mechanisms, depletion of DEL-1 does not impact coagulation under normal physiological conditions but leads to enhanced coagulation in disease states characterized by pathological increases in particulate production (Dasgupta et al., 2012a). DEL-1 can selectively disrupt the interaction between Mac-1 integrins on leukocytes and platelets, thereby inhibiting the thrombotic inflammatory injury that can arise, for instance, during myocardial infarction when platelet-leukocyte aggregates contribute to thrombosis (Kourtzelis et al., 2016). Romanidou et al. reported that in pregnant patients with thrombotic microangiopathy, circulating DEL-1 levels are significantly diminished and may represent a significant biomarker (Romanidou et al., 2023). Although the specific mechanism by which the reduction in circulating DEL-1 contributes to this type of widespread systemic thrombosis has not been identified at this time, the clearance of PMPs by DEL-1 and inhibiting the associated inflammation and thrombosis may hold therapeutic potential in preventing thrombosis or vascular injury associated with the pathological state.

The endoplasmic reticulum (ER) plays a key role in the synthesis, folding, and structural modification of proteins in cells (Schwarz and Blower, 2016). The endoplasmic reticulum stress (ER stress) response is a key regulator of inflammation and cell death. The capability of the ER to fold proteins varies greatly between cell types. When misfolded proteins accumulate in the endoplasmic reticulum, the ability of the ER to correctly fold and posttranslationally modify proteins can be compromised, leading to substantial cellular dysfunction which can contribute to both genetic mutations and vulnerability to environmental stressors (Wiseman et al., 2022). To maintain normal protein folding homeostasis, the endoplasmic reticulum activates the unfolded protein response (UPR) (Ron and Walter, 2007). However, excessive production of UPR signaling molecules can be detrimental. Persistent engagement of the UPR signaling cascade within the endoplasmic reticulum can also lead to an accumulation of misfolded proteins, resulting in ER stress (Oakes and Papa, 2015).

Prolonged ER stress can lead to an increased protein load and, if unmitigated, can ultimately result in cell death (Marciniak and Ron, 2006). Currently, two primary approaches target ER stress: one involves directly influencing the accumulation of misfolded proteins within the ER. While the other modulates the signaling of the unfolded protein response (UPR) via ER stress sensors or enzymes that regulate their downstream effects (Marciniak et al., 2022). The UPR is regulated by three endoplasmic reticulum transmembrane sensors: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). These factors are crucial for mediating the UPR and coordinating the cellular response to ER stress (Yap et al., 2021). Overexpression of DEL-1 has been shown to attenuate LPS-induced oxidative stress (Li et al., 2022b). In addition, DEL-1 attenuated palmitate-induced and HFD-induced skeletal muscle ER stress and insulin resistance via SIRT1/SERCA2-mediated signaling (Sun et al., 2020).

The AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor delta (PPARδ) are key regulatory proteins within the cell (Kemmerer et al., 2015). Downregulation of this signaling could promote ER stress-induced vascular endothelial dysfunction in adult rat offspring exposed to maternal diabetes (Luo et al., 2022). DEL-1 counteracts ER stress by activating the AMPK pathway, which, in turn, induces autophagy—a crucial defense mechanism that helps preserve cellular function. Additionally, DEL-1 protects tendon cells from stress-induced apoptosis (Park et al., 2022) (see Figure 2).

Within the vasculature, vascular smooth muscle is situated in the middle layer of the vessel and controls vasoconstriction and diastole. However, deviations from normal physiological activity in vascular smooth muscle can induce phenotypic transformation or diminish VSMC populations. Such changes can concurrently injure the endothelium, undermining vascular integrity (Baumann et al., 1981; Kuang et al., 2016; Grewal et al., 2021). Emerging evidence highlights that ER stress in VSMCs contributes to the progression of various vascular diseases through the release of extracellular vesicles and the disruption of autophagy; these diseases include vascular calcification and aortic dissection (Clement et al., 2019; Li et al., 2021b; Furmanik et al., 2021). In response to pathogenic stimuli, VSMCs may undergo phenotypic transformation into macrophage-like cells, a process often driven by the accumulation of lipids within atherosclerotic plaques (Bennett et al., 2016).

Mild or transient ER stress caused by the accumulation of misfolded or unfolded proteins, binding immunoglobulin protein (BiP) dissociates from IRE1α and ATF6 but remains bound to PERK. Then, IRE1α dimerizes and is phosphorylated, leading to the splicing of X-box binding protein 1 (XBP-1) (Cubillos-Ruiz et al., 2017). Notably, this factor inhibits pathological processes, including oxidative stress in endothelial cells and autophagy in VSMCs (Zhao et al., 2013; Martin et al., 2014). Concurrently, BiP dissociation triggers the translocation and cleavage of ATF6. If ER stress persists, BiP will also dissociate from PERK. This action induces the phosphorylation of the downstream protein eukaryotic translation initiation factor 2α (eIF2α), which is a crucial step in the ER stress response. This leads to the activation of the transcription factor C/EBP homologous protein (CHOP), which initiates the apoptotic pathway (Wu and Kaufman, 2006; Zhang et al., 2006; Cnop et al., 2017). In the case of atherosclerosis, prolonged and intensified ER stress contributes to sustained and enhanced UPR signaling, leading to cell death and exacerbating plaque formation in the arteries (Zhou and Tabas, 2013). Disturbed ER homeostasis triggers the progression of cardiovascular disease, which ultimately further exacerbates ER stress, creating a vicious circle (Ren et al., 2021).

Increased salivary gland CHOP expression in Sjögren’s syndrome (SS) is implicated in the promotion of apoptosis and in enhancing leukocyte infiltration. This upregulation correlates with decreased DEL-1 levels, providing mechanistic insight into the relationship between CHOP and DEL-1 (Baban et al., 2013). Inhibition of unspliced XBP1 (XBP1u) increases vascular calcification and stimulates ER stress to promote vascular remodeling. XBP1u interacts with β-catenin and promotes its degradation via the ubiquitin-proteasome pathway. This interaction inhibits the transcriptional activity of the beta-catenin/TCF complex, which is responsible for regulating osteogenic markers such as runt-related transcription factor 2 (Runx2) and Msh homeobox 2 (Msx2), which play roles in vascular calcification (Yang et al., 2022). When the autophagy protein 5 (Atg5) gene is absent in VSMCs, autophagy is impaired, increasing the susceptibility of VSMCs to cell death. This impairment in autophagy enhances ER stress activation, subsequently promoting inflammation in VSMCs through an IRE-1α-dependent mechanism (Clement et al., 2019). Cholesterol contributes to ER stress, which can trigger the conversion of VSMCs into cells exhibiting features characteristic of macrophages and fibroblasts, a process modulated by the UPR (Chattopadhyay et al., 2021).

Available evidence suggests that DEL-1 contributes to the inhibition of ER stress-induced apoptosis (Park et al., 2022). Recently, DEL-1 levels have been observed to be elevated in response to exercise, by inhibiting ER stress. This inhibition can contribute to reduced inflammation and improved insulin sensitivity, as indicated by evidence (Kwon et al., 2020). However, to date, no specific research has explored the ability of DEL-1 to alleviate ER stress in VSMCs. It is important to note that the ER in skeletal muscle is referred to as the sarcoplasmic reticulum (SR). Skeletal muscle fibers contain the sarcoplasmic reticulum, a highly differentiated structure composed of tubular networks aligned with sarcomeres, reflecting distinct morphological and structural characteristics compared to vascular smooth muscle (Cusimano et al., 2009; Sorrentino, 2011). In contrast, the ER in vascular smooth muscle, while lacking the specialized alignment of the SR, presents a reticulated network that pervades the entire cell. Investigating whether these structural differences influence the outcomes of DEL-1 intervention in VSMCs could provide valuable insights for therapeutic strategies. In addition to mitigating ER stress, DEL-1 may also protect against damage to VSMCs induced by other signaling pathways. For instance, signaling by he receptor activator ofnuclear factor kappa-beta ligand (RANKL) and the cytoplasmic calcineurin-dependent nuclear factor of activated T-cells (NFATc1) has been shown to facilitate the upregulation of bone morphogenetic proteins (BMPs) (Panizo et al., 2009; Singh et al., 2012; Shiny et al., 2016). Furthermore, DEL-1 has been demonstrated to inhibit the RANK-NFATc1 signaling axis, thus impeding osteoblast activation (Shin et al., 2015). This interaction likely represents a crucial mechanism by which DEL-1 sustains vascular integrity and health. The paracrine signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is likely to play an instrumental role in mediating the vasoprotective effects of DEL-1.

In various vascular diseases, inflammation is a crucial factor in promoting a spectrum of pathological changes (An et al., 2019). DEL-1 regulates the production of inflammatory factors and the activation of signaling pathways, thereby attenuating the impact of immune cells and their associated inflammation on the vasculature (Li et al., 2021a). The current evidence on the therapeutic potential of DEL-1 for cardiovascular disease remains a subject of debate. This controversy highlights the necessity for more rigorous clinical studies and mechanistic research to clarify the therapeutic benefits of DEL-1 in cardiovascular pathology (Zhao et al., 2022).

Further exploration of DEL-1 as a potential clinical therapeutic target or biomarker for vascular diseases is warranted. The differences in the expression and function of DEL-1 in different organs suggest that assessing its viability as a therapeutic target could be an important direction for future research (Figure 3). Amidst the ongoing debate on the use of DEL-1, its capacity to suppress inflammation and cytotoxicity should be acknowledged as a therapeutic option for cardiovascular diseases, targeting multiple cell types including ECs and VSMCs (Wang et al., 2022b). Further research is required to develop treatment modalities or drug delivery methods. This would allow the investigation of crosstalk between DEL-1 and other regulators of angiogenesis, thereby advancing our understanding of the role of DEL-1 in cardiovascular disease treatment (Cabrera and Makino, 2022; Zhao et al., 2022).

Conditional Knockout of the EDIL3 gene using CRISPR/Cas9 gene-editing technology may help assess the effects of DEL-1 on downstream signaling molecules byreducing the interference from any compensatory mechanisms or indirect signaling pathways, assessing functional changes in the intima, media, and adventitia layers of the vasculature (Wang et al., 2022b; Li et al., 2023b). The immunomodulatory effects of DEL-1 vary among cell types and environments, highlighting its immune plasticity. Although a connection has been identified between DEL-1 and specific vasoactive factors in angiogenesis (Niu et al., 2023), the interplay between DEL-1 and other molecules remains poorly understood. As vascular tissue engineering moves toward clinical applications, replicating vascular physiological function is one of the key barriers (Ciucurel and Sefton, 2014; Margolis et al., 2023). There have been limited studies exploring the use of DEL-1 in tissue engineering constructs to regulate endothelial cells (Ciucurel and Sefton, 2014). Looking forward, endogenous factors like DEL-1 mayprove crucial for the fabrication of a multiscale vascular hierarchy under physiological conditions. While DEL-1 has shown promising safety results in a clinical study (Grossman et al., 2007), our incomplete understanding of its physiological functions underscores the need for refined animal experiments to comprehensively determine its effects on various systems before advancing to further clinical trials.