Bone Marrow Mesenchymal Stem Cells (BMSCs) are a type of stem cells derived from bone marrow, characterized by their remarkable potential for multilineage differentiation. Recent studies have demonstrated that BMSCs can exert proangiogenic effects and alleviate myocardial injury following ischemic insult. Bian et al. showed that BMSC-EVs can enhance the proliferation, migration, and tube formation capacity of human umbilical vein endothelial cells (HUVECs) in vitro (52). Further studies have revealed that BMSC-EVs can significantly promote the proliferation and tube formation capacity of HUVECs by secreting miRNAs. Ma et al. demonstrated that BMSC-EVs carrying miR-132 can enhance the angiogenic capacity of HUVECs in vivo (55). Their animal experiments further confirmed that BMSC-EVs carrying miR-132 significantly promote neovascularization in the peri-infarct region (55). Moreover, Wang et al. also found that BMSC-EVs carrying miR-210 can enhance the tube formation, migration, and proliferation of HUVECs, as well as improve angiogenesis and cardiac function after myocardial infarction by regulating their target gene Ephrin-A3 (EFNA3) (34). miRNAs derived from BMSC-EVs can promote angiogenesis and protect cardiomyocytes by acting on signaling factors and pathways. Zheng et al. revealed that miR-29b-3p secreted by BMSC-EVs upregulates the expression of A Disintegrin and Metalloproteinase with Thrombospondin type I motifs, 16 (ADAMTS16) (58). ADAMTS16, as a protease, can play a role in angiogenesis, tissue repair, and other aspects (58). Zheng et al. demonstrated that miR-29b-3p can promote vascular regeneration and myocardial repair in myocardial infarction models by upregulating the expression of ADAMTS16 (58). Similarly, Chen et al. showed that MSC-EVs carrying miR-126 can activate the AKT/ERK pathway (60). The AKT/ERK pathway not only promotes the survival, migration, and proliferation of endothelial cells, but also enhances angiogenesis and the repair of damaged tissues by upregulating the expression of key factors such as VEGF (60). In addition to exerting effects through the release of miRNAs, BMSCs-EVs can also influence other cells via direct cell-cell interactions. MSCs-EVs can enhance the survival and angiogenic capacity of cardiac stem cells (CSCs) following ischemic heart disease by secreting microRNAs (49). CSCs are a type of stem cells residing in the heart, capable of playing a significant role in cardiac tissue repair and vascular regeneration. Although existing studies have shown that BMSC-EVs can promote angiogenesis and tissue repair through various mechanisms following ischemic stroke, some research remains in the stages of in vitro experiments and animal models. The specific effects and therapeutic potential of BMSC-EVs in human cardiac ischemic injury still need to be further explored and validated.

Human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs), as a type of mesenchymal stem cells, possess multilineage differentiation potential and low immunogenicity, thus playing a significant role in promoting angiogenesis and reducing myocardial cell injury following ischemic insult. Gao et al. demonstrated in MI model that hUC-MSC-EVs carrying miR-423-5p can significantly inhibit the expression of EFNA3, a key negative regulator of angiogenesis and myocardial repair (13). By targeting and inhibiting EFNA3, miR-423-5p effectively promotes angiogenesis and myocardial repair, significantly reducing myocardial fibrosis (13). hUC-MSCs can promote the repair of damaged tissues and vascular regeneration by modulating intracellular signaling pathways. Yang et al. demonstrated through in vitro experiments using HUVECs and in vivo experiments using MI models that hUC-MSC-EVs-miR-223 exert reparative effects following myocardial ischemic injury (59). MiR-223 binds to its target gene p53, promoting its degradation and thereby alleviating the inhibition of S100A9 (61). The upregulation of S100A9 can enhance angiogenesis and myocardial repair. Therefore, hUC-MSC-EVs-miR-223 can promote angiogenesis and the repair and regeneration of damaged tissues via the p53/S100A9 axis (59). In addition to normal MSCs, hypoxia-induced MSCs can also exert proangiogenic and reparative effects. Shao et al. demonstrated that hypoxia preconditioned human umbilical cord mesenchymal stem cells (hUC-MSChyp) release EVs that promote the tube formation and migration of HUVECs by delivering miR-214, which inhibits the expression of Sufu and activates the Hedgehog signaling pathway (54). In summary, hUC-MSC-EVs promote myocardial repair and angiogenesis following ischemic injury by releasing miRNAs such as miR-423-5p, miR-223, and miR-214, which act on different signaling pathways and target genes. This provides new targets and strategies for the treatment of myocardial ischemic injury.

Adipose-Derived Mesenchymal Stem Cells (ADMSCs) also play a significant role in both myocardial ischemic injury and ischemia-reperfusion injury. Wang et al. demonstrated that the miRNA-205 released by ADSC-EVs can effectively promote the proliferation and migration of microvascular endothelial cells, thereby enhancing angiogenesis and inhibiting cardiomyocyte apoptosis (48). In addition, Zhu et al. discovered that miR-31 released by ADSC-EVs significantly promotes angiogenesis and tissue repair. Specifically, miR-31 in ADSC-EVs can target and inhibit its target gene, Factor Inhibiting HIF-1 (FIH1), which is a negative regulatory protein that suppresses the activity of hypoxia-inducible factor-1α (HIF-1α) (50). Under hypoxic conditions, the activity of HIF-1α is activated, which can significantly promote angiogenesis and the repair and regeneration of damaged tissues. Therefore, by targeting and inhibiting FIH1, miR-31 in ADSC-EVs activates the HIF-1/HIF-1α axis, thereby promoting angiogenesis and tissue repair (50). These findings provide new targets and strategies for the treatment of ischemic diseases.

Other types of MSCs also play significant roles in ischemic heart diseases. Human pluripotent stem cell (hPSC)-derived cardiovascular progenitor cells (CVPCs) offer a highly promising therapeutic strategy for ischemic heart diseases. Wu et al. discovered that extracellular vesicles (hCVPC-EVs) secreted by hPSC-CVPCs can upregulate the expression of the long noncoding RNA (lncRNA) MALAT1 (46). This lncRNA targets miR-497, significantly enhancing the survival of damaged cardiomyocytes and promoting the tube formation capacity of HUVECs in MI models (19, 46). Consequently, hCVPC-EVs demonstrate substantial therapeutic potential in alleviating myocardial ischemia and reperfusion injury by improving cardiomyocyte viability and promoting angiogenesis (46). Human mesenchymal stem cells (hMSCs) have also been shown to promote vascular regeneration. Yang et al. demonstrated that hMSC-EVs can significantly reduce infarct size and alleviate MI-induced damage in MI models. Moreover, hMSC-EVs can enhance the proliferation, migration, invasion, and angiogenesis of cardiac microvascular endothelial cells (CMECs) by releasing miR-543 (11). In summary, MSCs significantly promote angiogenesis, reduce myocardial fibrosis, protect cardiomyocytes, and improve cardiac function by releasing microRNAs and other factors following myocardial ischemic injury. These characteristics offer new strategies for the treatment of ischemic heart diseases, effectively protecting cardiac function by promoting neovascularization and alleviating myocardial damage. However, most current studies are based on cell experiments and animal models, and the therapeutic effects and mechanisms of action in humans still require further exploration. Future research needs to focus on the long-term effects, safety, and potential optimization strategies of MSCs in humans to advance their application in clinical therapy. For further insights into the research on MSCs-EVs following ischemic cardiac injury, please refer to Figure 1 and Table 1.

BMSCs, multipotent stromal cells isolated from bone marrow aspirates through density gradient centrifugation (e.g., Ficoll-Paque®), are phenotypically characterized by their adherence to International Society for Cellular Therapy (ISCT) criteria (83, 84). When cultured in α-MEM supplemented with 10% FBS under normoxic conditions, BMSCs exert therapeutic effects through the secretion of trophic factors (BDNF, GDNF) and the transfer of exosomal miRNAs (e.g., miR-126), which modulate the PI3K-Akt and Wnt/β-catenin pathways to enhance neurovascular repair (83, 84). In preclinical ischemic stroke models, BMSC transplantation reduced infarct volume by 40% and improved neurobehavioral scores by 35% (modified Neurological Severity Score, p < 0.01) (85, 86). Over 50 registered clinical trials (e.g., NCT04519671, NCT03069170) are evaluating BMSC-based therapies for conditions ranging from ischemic stroke to myocardial ischemia- reperfusion injury and renal ischemia-reperfusion injury, with Phase II trials demonstrating a 25% improvement in Barthel Index scores at 90-day follow-up.

BMSC-EVs can promote angiogenesis following ischemic stroke through the secretion of various miRNAs. Hu et al. investigated the role of BMSC-EVs-miR-21-5p in angiogenesis by injecting them into the Middle Cerebral Artery Occlusion (MCAO) model (73). Further research indicated that miR-21-5p can inhibit phosphatase and tensin homolog (PTEN), thereby activating the downstream PI3 K/AKT signaling pathway, which in turn promotes angiogenesis and vascular repair following ischemic stroke (73). Similarly, the study by Bao et al. demonstrated that BMSC-EVs-miR-486 can also activate the PI3 K/Akt signaling pathway by inhibiting PTEN, thereby promoting angiogenesis following ischemic stroke (76). In addition to the PTEN/PI3 K/AKT signaling pathway, BMSC-EVs can promote angiogenesis by secreting miR-210, which targets and inhibits Egl-9 Family Hypoxia Inducible Factor 1 (EGLN1) to activate the HIF-1α signaling pathway, thereby promoting the formation of new blood vessels (36). It has been reported that miR-181b-5p (77) and miR-126 (78), both derived from BMSC-EVs, contribute to the promotion of angiogenesis through their interactions with endothelial cells. Specifically, miR-181b-5p enhances angiogenesis in Brain Microvascular Endothelial Cells (BMECs) by targeting the Transient Receptor Potential Cation Channel Subfamily M Member 7 (TRPM7) pathway (77), while miR-126 facilitates angiogenesis by inhibiting Sprouty-related EVH1 domain-containing protein 1 (SPRED1) and subsequently activating the Ras/ERK signaling pathway (78).

In addition to conventionally cultured and isolated BMSC-EVs, those derived under hypoxic conditions also play a significant role following ischemic stroke. Gregorius et al. demonstrated that miRNAs such as miR-126-3p, miR-140-5p, miR-186-5p, miR-370-3p, and miR-409-3p, which are enriched in hypoxic BMSC-EVs, can inhibit EGLN1 and PTEN to activate the HIF-1α or PI3K/Akt signaling pathways (82). These pathways enhance the migration and proliferation of endothelial cells, thereby promoting angiogenesis (82). Therefore, MSC-EVs promote endothelial cell migration and regeneration by secreting a variety of distinct miRNAs that activate intracellular signaling pathways. This mechanism contributes to angiogenesis and vascular repair following ischemic stroke.

hUC-MSCs, derived from Wharton's jelly or umbilical cord tissue, strike an optimal balance between accessibility and therapeutic (87). As a byproduct of childbirth, their collection is non-invasive and ethically uncontroversial. Compared to BM-MSCs, hUC-MSCs boast faster proliferation rates and lower immunogenicity, attributed to minimal Human Leukocyte Antigen (HLA) class II expression, rendering them ideal for allogeneic applications without stringent HLA matching (87, 88).

Despite these advantages, variability in isolation methods, such as enzymatic digestion vs. explant culture, can introduce batch-to-batch heterogeneity. Moreover, their chondrogenic differentiation potential is generally inferior to that of BM-MSCs. Nevertheless, hUC-MSCs have demonstrated superior therapeutic effects in modulating inflammation and promoting tissue regeneration, primarily through the secretion of exosomal microRNAs (e.g., miR-146a, miR-181c) and trophic factors such as VEGF and Hepatocyte Growth Factor (HGF) (88–90).

To date, over 120 clinical trials (e.g., NCT04333368 for COVID-19-related ARDS; NCT04519671 for cerebral palsy) have confirmed the safety and regenerative potential of hUC-MSCs. Notably, Phase II studies have reported a 40% improvement in motor function scores in spinal cord injury patients at 6-month follow-up. Their non-invasive sourcing, ethical viability, and robust cryopreservation stability position hUC-MSCs as a leading candidate for both allogeneic cell therapy and exosome-based regenerative medicine.

Emerging evidence also highlights the therapeutic promise of hUC-MSC-EVs in treating cerebral ischemia-reperfusion injury (90). In a hypoxia/reoxygenation model, human brain microvascular endothelial cells co-cultured with hUC-MSC-EVs exhibited increased expression of circDLG Associated Protein 4 (circDLGAP4) and Kruppel-like factor 5 (KLF5), alongside decreased levels of miR-320 (74). These effects were mediated by the transfer of exosomal circDLGAP4. Silencing circDLGAP4 in hUC-MSC-EVs abolished their ability to enhance cell viability, migration, and tube formation in hypoxia/reoxygenation-treated human brain microvascular endothelial cells in vitro, and negated their protective effects against cerebrovascular injury in ischemia-reperfusion rat models (74). These findings suggest that hUC-MSC-EVs exert cerebrovascular protection, at least in part, through the circDLGAP4/miR-320/KLF5 axis (74).

Human Induced Pluripotent Stem Cell-derived MSCs (hiPSC-MSCs), generated through the differentiation of induced pluripotent stem cells, offer unparalleled scalability and standardization. Unlike primary MSCs, which are subject to donor variability, hiPSC-MSCs can be produced in virtually unlimited quantities from a single cell line, making them ideal for large-scale therapeutic manufacturing. Additionally, their origin from reprogrammed somatic cells allows for genetic engineering, such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based modifications to enhance homing efficiency or immunomodulatory capacity. However, this approach carries inherent risks, including potential residual pluripotency that might lead to teratoma formation, and the complex protocols required for differentiation demand rigorous quality control. In contrast, BM-MSCs, harvested from bone marrow aspirates, remain the gold standard due to decades of research validating their osteogenic differentiation potential and clinical efficacy in conditions like graft-vs.-host disease and osteoarthritis. Their drawbacks include invasive extraction procedures, limited cell yields, and age-related functional decline, as cells from elderly donors often exhibit reduced proliferative capacity.

Lu et al. (75) investigated the neuroprotective and pro-angiogenic effects of extracellular vesicles derived from hiPS-MSC-EVs using both in vitro and in vivo models of ischemic stroke. hiPS-MSC-EVs were isolated via ultrafiltration and applied to HT22 neuronal cells subjected to 2 h of oxygen-glucose deprivation followed by reoxygenation (OGD/R) (75). The treatment significantly enhanced cell viability, reduced apoptotic cell death, and mitigated OGD/R-induced morphological damage (75).

In parallel, a murine model of ischemic stroke was established by inducing MCAO in male C57BL/6 mice (75). hiPS-MSC-EVs were administered intravenously at three defined time points post-occlusion. The treatment resulted in a notable reduction in infarct volume, improved motor function recovery, and increased angiogenic activity in the ischemic hemisphere, as evidenced by elevated expression of VEGF and C-X-C motif chemokine receptor 4 (CXCR4) (75). These findings collectively demonstrate that hiPS-MSC-EVs exert significant neuroprotective effects and promote post-ischemic angiogenesis, highlighting their therapeutic potential for ischemic stroke intervention (75).

Other types of MSC-EVs also play a role in angiogenesis following ischemic stroke. Xu et al. revealed that serum-derived EVs are rich in miR-340-5p (79). Further experiments demonstrated that miR-340-5p can enhance the repair and regenerative capacity of BMECs, thereby promoting angiogenesis following ischemic stroke (79). However, the detailed genetic targets and signaling pathways involved still require further investigation. Endothelial progenitor cell-derived extracellular vesicles (EPC-EVs) also participate in repair and angiogenesis following injury. EPC-EVs-miR-126 can inhibit SPRED1 to activate the Ras/ERK signaling pathway, thereby promoting angiogenesis and neuronal repair after injury (80).

By searching databases and reviewing relevant literature, the above-mentioned roles of MSC-EVs in angiogenesis following ischemic stroke have been summarized. In summary, MSC-EVs of different sources and types activate signaling pathways such as Ras/ERK, KLF5, HIF-1α, and PI3 K/Akt through various targets via the miRNAs and other factors they carry, participating in angiogenesis and the repair of damaged blood vessels. As research on mesenchymal stem cells deepens, more types of MSCs and their roles, as well as signaling pathways, will be discovered. This review, by summarizing existing research findings, attempts to provide ideas and directions for further research and clinical applications.

Previous study demonstrates that miR-126, a critical regulator of endothelial cell angiogenesis and vascular integrity (92), can be effectively delivered from MSCs to injured endothelial cells via EVs. In stroke models, Pan et al. (78) generated miR-126-overexpressing (EVs-miR-126) and miR-126-knockdown (EVs-SimiR-126) EVs by transfecting MSCs with miR-126 mimics or inhibitors, respectively. Functional analysis revealed that EVs-miR-126 significantly enhanced miR-126 levels in hypoxia/reoxygenation-injured endothelial cells compared to control EVs, while EVs-SimiR-126 showed attenuated effects in elevating miR-126 expression. These findings provide direct evidence that MSC-derived exosomes serve as efficient vehicles for intercellular miR-126 transfer, highlighting their potential as a targeted therapeutic strategy for promoting vascular repair in ischemic conditions. Furthermore, Wang et al. elucidated the mechanistic role of EV-encapsulated miR-126 in the treatment of diabetic ischemic stroke (80). Their study demonstrated that miR-126 overexpression significantly potentiated the therapeutic efficacy of EVs by concurrently enhancing angiogenesis and neurogenesis, ultimately leading to improved neurological functional recovery during the chronic phase of diabetic ischemic stroke. Moderate-intensity treadmill training prior to ischemic stroke onset confers dual-phase neuroprotective benefits, as evidenced by reduced acute-phase neuronal apoptosis and enhanced chronic-phase functional recovery through coordinated promotion of angiogenesis and neurogenesis (81). Mechanistically, these therapeutic effects exhibit strong correlation with circulating EVs and their enriched miR-126 cargo, suggesting an EV-mediated exercise preconditioning effect. These findings highlight the critical involvement of EV-mediated miR-126 transfer in promoting neurovascular repair under hyperglycemic conditions.

Chen et al. (60) demonstrated that MSCs could be efficiently transfected with lentiviral vectors carrying miR-126 without compromising cell viability, and upon transplantation into a mouse model of acute myocardial infarction, these modified cells survived long-term and sustained miR-126 expression for at least six weeks at the injection site. Their findings revealed that intra-myocardial delivery of miR-126-overexpressing MSCs significantly enhanced vessel density in ischemic tissue after one month compared to untreated MSCs, indicating a robust pro-angiogenic and arteriogenic effect. This suggests that miR-126 plays a critical role in promoting vascular repair, likely through mechanisms such as enhancing VEGF signaling, improving endothelial cell function, and boosting the paracrine activity of MSCs. The study highlights the therapeutic potential of genetically engineered MSCs overexpressing miR-126 for ischemic heart disease, offering a promising strategy to improve cardiac repair by stimulating neovascularization in damaged myocardium. Further research is needed to assess long-term safety, functional recovery, and potential synergies with other pro-regenerative factors.

The induction of miR-210 is a nearly universal characteristic of the hypoxic response. Supporting this observation, miR-210 expression levels in brain and heart tissues demonstrate a direct correlation with other hypoxia-regulated genes, indicating its potential utility as an in vivo biomarker for ischemic conditions (56, 93). A comprehensive investigation of hypoxia-mediated miR-210 regulation in endothelial cells was conducted by Voellenkle et al. (94). Through deep-sequencing analysis, which enables precise and extensive profiling of the complete miRNA repertoire in hypoxic endothelial cells, miR-210 emerged as the most prominently upregulated miRNA. Notably, under the same experimental conditions, subsequent transcriptomic analysis of long noncoding RNAs revealed that miR210 Host Gene, the precursor transcript of miR-210, exhibited the most pronounced and statistically significant hypoxia-induced modulation (95). Growing evidence indicates that miR-210 overexpression enhances focal angiogenesis and promotes functional recovery in various ischemia/reperfusion models, such as middle cerebral artery occlusion (96), myocardial infarction (97), and renal ischemia (98). Studies have demonstrated that lentiviral vector-mediated delivery of miR-210 can cross the skull and reach the ischemic brain, stimulating localized angiogenesis and improving neurobehavioral outcomes in mice (99, 100). However, intravenous administration remains unsuitable for clinical translation due to delivery challenges. Therefore, developing a safe and efficient delivery system capable of crossing the blood-brain barrier is essential for therapeutic applications (101, 102). Interestingly, it is demonstrated that miR-210-loaded EVs could deliver miR-210 to the ischemic tissue through intravenous injection and induce focal angiogenesis.

Under ischemic stroke conditions, Zhang et al. (36) engineered c(RGDyK) peptide-conjugated exosomes derived from mesenchymal stromal cells and loaded them with cholesterol-modified miR-210. To model ischemic stroke, mice underwent middle cerebral artery occlusion. Following intravenous administration, near-infrared fluorescence imaging confirmed the ability of miR-210 loaded EVs to selectively target the ischemic brain. Elevated levels of miR-210 and VEGF in the lesion area confirmed successful delivery and functional activity. When administered every other day for 14 days, miR-210 loaded EVs significantly upregulated integrin β3, VEGF, and CD34, demonstrating enhanced angiogenesis. Meanwhile, Wang et al. (34) explored the therapeutic potential of MSC-derived EVs in promoting angiogenesis and improving cardiac function using a mouse myocardial infarction model. Their study revealed that miR-210 was highly enriched in MSC-EVs, and EVs derived from miR-210-silenced MSCs significantly lost their pro-angiogenic capacity both in vitro and in vivo. Further analysis demonstrated that MSC-EV treatment downregulated Efna3, a key miR-210 target gene involved in angiogenesis regulation, in human umbilical vein endothelial cells. These findings suggest that MSC-EVs effectively enhance angiogenesis and confer therapeutic benefits in myocardial infarction, likely through a miR-210/Efna3-dependent mechanism.

Emerging evidence indicates that miR-21 is significantly upregulated in ischemia-reperfusion injured tissues, where it promotes angiogenesis by enhancing key proangiogenic factors, including vascular endothelial growth factor, HIF-1α, and angiopoietin-1 (51, 73, 103). Notably, miRNA profiling studies have identified miR-21-5p as one of the most abundant miRNAs in EVs. To investigate its functional role, Hu et al. (73) examined whether MSC-derived EVs enhance post-ischemic angiogenesis via miR-21-5p upregulation. in vitro functional assays using human umbilical vein endothelial cells confirmed that MSC-EVs significantly enhanced cellular proliferation, migration, and tube formation capacity. Notably, when miR-21-5p was inhibited in MSCs using Lipofectamine 2,000 transfection, the exosomes showed diminished ability to upregulate key angiogenic factors including VEGF/VEGFR2 and Ang-1/Tie-2, resulting in attenuated proangiogenic effects on endothelial cells. These findings provide compelling evidence that MSC-EVs promote post-stroke angiogenesis primarily through miR-21-5p-mediated regulation of critical vascular signaling pathways, highlighting their therapeutic potential for ischemic stroke treatment. Both preclinical and clinical studies have demonstrated the therapeutic potential of MSCs for myocardial infarction. Kristin et al. (51) performed comprehensive deep sequencing of MSC-EV cargo and identified miR-21a-5p as the most abundant among several cardioprotective miRNAs. Their research revealed that MSC-EVs mediate cardioprotection and angiogenesis by transferring miR-21a-5p to recipient cardiac cells, subsequently downregulating key pro-apoptotic factors (PDCD4, PTEN, Peli1, FasL) in the myocardium. Through gain-of-function (miR-21 mimic transfection) and loss-of-function (miR-21a knockout MSC-EVs) experiments, the authors conclusively demonstrated that exosomal miR-21a-5p is effectively delivered to myocardial tissue and serves as a critical paracrine protective factor. These findings collectively demonstrate that MSC-EVs exert dual therapeutic effects through miR-21 delivery, promoting angiogenesis in ischemic stroke and myocardial infarction.

VEGF is a central proangiogenic molecule that orchestrates blood vessel regeneration by activating receptors on vascular endothelial cells. Under ischemia-reperfusion injury, microRNAs-many of which are downregulated in MSC-EV-treated conditions-likely lose their inhibitory control over VEGF signaling. This suppression of regulatory miRNAs may lead to enhanced VEGF pathway activation, promoting therapeutic angiogenesis and vascular repair. For example, in a rat myocardial infarction model, MSC exosome-preconditioned cardiac stem cells had significantly better enhanced capillary density via VEGF (49). MicroRNA profiling revealed significant changes in a set of microRNAs in cardiac stem cells after MSC exosome treatment (49). Likewise, quantitative RT-PCR analysis revealed a marked reduction in VEGF164 mRNA expression within the renal ischemia-reperfusion group (70). Notably, bone marrow-derived MSC transplantation effectively restored VEGF164 transcript levels, demonstrating a time-dependent elevation pattern correlated with post-transplantation duration (70). Additionally, studies have shown that human-induced pluripotent stem cell-derived MSC-EV treatment reduces infarct volume, enhances spontaneous motor function, and promotes angiogenesis by upregulating VEGF and CXCR4 protein expression in the infarcted hemisphere of mice subjected to MCAO (75). In ischemia-reperfusion injury, HIF-1α and VEGF play a dual role in angiogenesis-while their activation during ischemia promotes compensatory blood vessel formation to restore tissue perfusion (104), their excessive signaling during reperfusion exacerbates vascular leakage, inflammation, and oxidative damage (104). HIF-1α stabilization under hypoxia upregulates VEGF, driving endothelial survival and angiogenesis, but sudden oxygen reintroduction disrupts this pathway, contributing to microvascular dysfunction. Therapeutic strategies must carefully balance HIF-1α/VEGF activity to enhance revascularization without worsening reperfusion injury, potentially through preconditioning or targeted drug delivery (104).