{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:45:33Z","timestamp":1790221533285,"version":"4.1.0"},"reference-count":76,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tianjin Science and Technology Bureau","award":["21JCYBJC01260"],"award-info":[{"award-number":["21JCYBJC01260"]}]},{"name":"Tianjin Science and Technology Bureau","award":["24JCQNJC00770"],"award-info":[{"award-number":["24JCQNJC00770"]}]},{"name":"Tianjin Science and Technology Bureau","award":["2021KJ128"],"award-info":[{"award-number":["2021KJ128"]}]},{"name":"Tianjin Education Commission","award":["21JCYBJC01260"],"award-info":[{"award-number":["21JCYBJC01260"]}]},{"name":"Tianjin Education Commission","award":["24JCQNJC00770"],"award-info":[{"award-number":["24JCQNJC00770"]}]},{"name":"Tianjin Education Commission","award":["2021KJ128"],"award-info":[{"award-number":["2021KJ128"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Intercellular communication, facilitated by exosomes (Exos) derived from endothelial cells (ECs), significantly influences the regulation of angiogenesis. Leech extract significantly reduces ischemia\u2013reperfusion injury, promotes angiogenesis, and improves neurological function in mice with stroke. However, further investigation is required to determine whether leech promotes angiogenesis through EC-Exo. Objective: This study aims to further explore whether leech regulates Exos to promote the establishment of collateral circulation in mice with ischemic stroke (IS) and the specific mechanisms involved. Methods: Here, we utilized an in vitro co-culture system comprising ECs and pericytes to investigate the impact of Leech-EC-Exo on enhancing the proliferation and migration of mouse brain microvascular pericytes (MBVPs). We further established an in vivo mouse model of middle cerebral artery occlusion\/reperfusion (MCAO\/R) to investigate the effects and underlying mechanisms of leech on collateral circulation establishment. Results: The findings demonstrated that leech significantly enhanced the in vitro cell migration number and migration number of pericytes. Therefore, it can also enhance the effect of EC-Exo on improving the infarct area and gait of mice, as well as modulating the HIF\u03b1-VEGF-DLL4-Notch1 signaling pathway to promote cerebral angiogenesis and facilitating the stable maturation of neovascularization in vivo. Conclusions: These results suggest that leech has the potential to enhance collateral circulation establishment, and its mechanism may involve the modulation of miRNA content in Exos and the promotion of signaling pathways associated with angiogenesis and vascular maturation.<\/jats:p>","DOI":"10.3390\/cimb47070499","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T04:04:22Z","timestamp":1751342662000},"page":"499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Leech Extract Enhances the Pro-Angiogenic Effects of Endothelial Cell-Derived Exosomes in a Mouse Model of Ischemic Stroke"],"prefix":"10.3390","volume":"47","author":[{"given":"Yushuang","family":"Cao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichen","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1762-8684","authenticated-orcid":false,"given":"Shaoxia","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Chai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Component Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 071000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0140-6736(20)31179-X","article-title":"Stroke","volume":"396","author":"Campbell","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1016\/j.apsb.2020.11.019","article-title":"Recent advances in nanomedicines for the treatment of ischemic stroke","volume":"11","author":"Li","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1007\/s12975-023-01182-0","article-title":"Application of Nanozymes and its Progress in the Treatment of Ischemic Stroke","volume":"15","author":"Han","year":"2024","journal-title":"Transl. Stroke Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhai, Z., Su, P.W., Ma, L.Y., Yang, H., Wang, T., Fei, Z.G., Zhang, Y.N., Wang, Y., Ma, K., and Han, B.B. (2023). Progress on traditional Chinese medicine in treatment of ischemic stroke via the gut-brain axis. Biomed. Pharmacother., 157.","DOI":"10.1016\/j.biopha.2022.114056"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Barthels, D., and Das, H. (2020). Current advances in ischemic stroke research and therapies. Biochim. Biophys. Acta Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2018.09.012"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1096\/fj.201601209R","article-title":"Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke","volume":"31","author":"Fukuta","year":"2017","journal-title":"FASEB J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e242401","DOI":"10.1148\/radiol.242401","article-title":"Arterial Collaterals and Endovascular Treatment Effect in Acute Ischemic Stroke with Large Infarct: A Secondary Analysis of the TENSION Trial","volume":"314","author":"Winkelmeier","year":"2025","journal-title":"Radiology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1148\/radiol.2020191712","article-title":"Multiphase MR Angiography Collateral Map: Functional Outcome after Acute Anterior Circulation Ischemic Stroke","volume":"295","author":"Kim","year":"2020","journal-title":"Radiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1016\/j.acra.2024.11.032","article-title":"Predicting Futile Recanalization by Cerebral Collateral Recycle Status in Patients with Endovascular Stroke Treatment: The CHANOA Score","volume":"32","author":"Gong","year":"2025","journal-title":"Acad. Radiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e2409361","DOI":"10.1002\/advs.202409361","article-title":"Non-Invasive Photoacoustic Cerebrovascular Monitoring of Early-Stage Ischemic Strokes In Vivo","volume":"12","author":"Kim","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.5853\/jos.2022.02936","article-title":"Collateral Circulation in Ischemic Stroke: An Updated Review","volume":"25","author":"Maguida","year":"2023","journal-title":"J. Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/s41401-023-01061-2","article-title":"Angiogenesis after ischemic stroke","volume":"44","author":"Fang","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3892\/etm.2025.12811","article-title":"Mechanism of disturbed endothelial cell function on angiogenesis following ischemic brain stroke (Review)","volume":"29","author":"Gong","year":"2025","journal-title":"Exp. Ther. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103490","DOI":"10.1016\/j.media.2025.103490","article-title":"Large vessel occlusion identification network with vessel guidance and asymmetry learning on CT angiography of acute ischemic stroke patients","volume":"101","author":"Kuang","year":"2025","journal-title":"Med. Image Anal."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mastrullo, V., Matos, R.S., McVey, J.H., Gupta, P., Madeddu, P., Johnston, J.D., Van Der Veen, D.R., Velliou, E.G., and Campagnolo, P. (2021). The vascular clock: A new insight into endothelial cells and pericytes crosstalk. Eur. Heart J., 42.","DOI":"10.1093\/eurheartj\/ehab724.3382"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jare.2024.01.016","article-title":"The role of endothelial cell-pericyte interactions in vascularization and diseases","volume":"67","author":"Li","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00109-022-02276-2","article-title":"EVs vs. EVs: MSCs and Tregs as a source of invisible possibilities","volume":"101","author":"Heydari","year":"2023","journal-title":"J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9330","DOI":"10.1002\/jcp.26413","article-title":"Extracellular vesicles derived from human embryonic stem cell-MSCs ameliorate cirrhosis in thioacetamide-induced chronic liver injury","volume":"233","author":"Mardpour","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, L., Yang, L., Tian, L., Guo, B., Dai, T., Lv, Q., Xie, J., Liu, F., Bao, H., and Cao, F. (2025). Exosome-capturing scaffold promotes endogenous bone regeneration through neutrophil-derived exosomes by enhancing fast vascularization. Biomaterials, 319.","DOI":"10.1016\/j.biomaterials.2025.123215"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1002\/jcb.26621","article-title":"Exosomes secreted by hypoxic cardiosphere-derived cells enhance tube formation and increase pro-angiogenic miRNA","volume":"119","author":"Namazi","year":"2018","journal-title":"J. Cell Biochem."},{"key":"ref_21","first-page":"85","article-title":"Research Progress of Leech Anticoagulant Components in the Treatment of Ischemic Stroke","volume":"41","author":"Li","year":"2024","journal-title":"Inf. Tradit. Chin. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1161\/ATVBAHA.111.227314","article-title":"Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues","volume":"31","author":"Faber","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","first-page":"147","article-title":"Pharmacological Action of Shuizhi (Leech) and Its Application in Encephalopathy","volume":"42","author":"Han","year":"2024","journal-title":"Chin. Arch. Tradit. Chin. Med."},{"key":"ref_24","first-page":"209","article-title":"Mechanism of Hirudo in Treatment of Stroke: A Review","volume":"29","author":"Xu","year":"2023","journal-title":"Chin. J. Exp. Tradit. Med. Formulae"},{"key":"ref_25","first-page":"47","article-title":"Research progress on the mechanism of leech in treating cardiovascular and cerebrovascular diseases","volume":"18","author":"Wang","year":"2021","journal-title":"China Med. Herald."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sun, J., Yuan, Q., Guo, L., Xiao, G., Zhang, T., Liang, B., Yao, R., Zhu, Y., Li, Y., and Hu, L. (2022). Brain Microvascular Endothelial Cell-Derived Exosomes Protect Neurons from Ischemia-Reperfusion Injury in Mice. Pharmaceuticals, 15.","DOI":"10.3390\/ph15101287"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zheng, T., Pu, J., Chen, Y., Mao, Y., Guo, Z., Pan, H., Zhang, L., Zhang, H., Sun, B., and Zhang, B. (2017). Plasma Exosomes Spread and Cluster Around \u03b2-Amyloid Plaques in an Animal Model of Alzheimer\u2019s Disease. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00012"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"116287","DOI":"10.1016\/j.jep.2023.116287","article-title":"Protective effect and underlying mechanism of muscone on acute cerebral ischemia-reperfusion injury in rats","volume":"308","author":"Zhang","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bertrand, L., Dygert, L., and Toborek, M. (2017). Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area. J. Vis. Exp.","DOI":"10.3791\/54805"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1161\/01.STR.27.9.1616","article-title":"Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model","volume":"27","author":"Belayev","year":"1996","journal-title":"Stroke"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1136\/svn-2020-000419","article-title":"Therapeutic application of exosomes in ischaemic stroke","volume":"6","author":"Li","year":"2021","journal-title":"Stroke Vasc. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.neuroscience.2020.05.046","article-title":"Vascular Endothelial Cell-derived Exosomes Protect Neural Stem Cells Against Ischemia\/reperfusion Injury","volume":"441","author":"Zhou","year":"2020","journal-title":"Neuroscience"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sun, X., Jung, J.H., Arvola, O., Santoso, M.R., Giffard, R.G., Yang, P.C., and Stary, C.M. (2019). Stem Cell-Derived Exosomes Protect Astrocyte Cultures From in vitro Ischemia and Decrease Injury as Post-stroke Intravenous Therapy. Front. Cell Neurosci., 13.","DOI":"10.3389\/fncel.2019.00394"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1001\/jama.2013.6959","article-title":"Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke","volume":"309","author":"Saver","year":"2013","journal-title":"JAMA"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Hwang, S., Choi, J., and Kim, M. (2019). Combining Human Umbilical Cord Blood Cells With Erythropoietin Enhances Angiogenesis\/Neurogenesis and Behavioral Recovery After Stroke. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00357"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1161\/hs1101.098367","article-title":"Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats","volume":"32","author":"Chen","year":"2001","journal-title":"Stroke"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15613","DOI":"10.1038\/ncomms15613","article-title":"Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss","volume":"8","author":"Quarta","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1161\/STROKEAHA.119.025371","article-title":"MiR-126 Mediates Brain Endothelial Cell Exosome Treatment-Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice","volume":"50","author":"Venkat","year":"2019","journal-title":"Stroke"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.neuroscience.2018.08.029","article-title":"SNHG12 Promotes Angiogenesis Following Ischemic Stroke via Regulating miR-150\/VEGF Pathway","volume":"390","author":"Zhao","year":"2018","journal-title":"Neuroscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.bbr.2016.05.031","article-title":"Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice","volume":"311","author":"Moon","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1080\/15384101.2020.1731655","article-title":"Chrysophanol protects PC12 cells against oxygen glucose deprivation-evoked injury by up-regulating miR-216a","volume":"19","author":"Liu","year":"2020","journal-title":"Cell Cycle"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/hr.2011.163","article-title":"Nitrergic nerves derived from the pterygopalatine ganglion innervate arteries irrigating the cerebrum but not the cerebellum and brain stem in monkeys","volume":"35","author":"Ayajiki","year":"2012","journal-title":"Hypertens. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.devcel.2008.07.008","article-title":"miR-126 regulates angiogenic signaling and vascular integrity","volume":"15","author":"Fish","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"113325","DOI":"10.1016\/j.expneurol.2020.113325","article-title":"Moderate exercise has beneficial effects on mouse ischemic stroke by enhancing the functions of circulating endothelial progenitor cell-derived exosomes","volume":"330","author":"Wang","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15878","DOI":"10.1074\/jbc.M800731200","article-title":"MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3","volume":"283","author":"Fasanaro","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9590","DOI":"10.1111\/jcmm.15387","article-title":"Extracellular vesicle-enclosed miR-486-5p mediates wound healing with adipose-derived stem cells by promoting angiogenesis","volume":"24","author":"Lu","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jhep.2012.04.031","article-title":"MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatoma","volume":"57","author":"Shih","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1002\/jcp.29214","article-title":"Upregulation of microRNA-218 reduces cardiac microvascular endothelial cells injury induced by coronary artery disease through the inhibition of HMGB1","volume":"235","author":"Gao","year":"2020","journal-title":"J. Cell Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Chang, W.T., Lin, Y.W., Huang, P.S., Lin, Y.C., Tseng, S.Y., Chao, T.H., Chen, Z.C., Shih, J.Y., and Hong, C.S. (2022). Deletion of MicroRNA-21 Impairs Neovascularization Following Limb Ischemia: From Bedside to Bench. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.826478"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"258","DOI":"10.21037\/atm-22-475","article-title":"Circulating exosomal miR-21 mediates HUVEC proliferation and migration through PTEN\/PI3K\/AKT in Crohn\u2019s disease","volume":"10","author":"Xie","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s10456-022-09856-3","article-title":"MicroRNA-375 repression of Kruppel-like factor 5 improves angiogenesis in diabetic critical limb ischemia","volume":"26","author":"McCoy","year":"2023","journal-title":"Angiogenesis"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1182\/blood-2013-02-478925","article-title":"Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells","volume":"121","author":"Smits","year":"2013","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"336","DOI":"10.5603\/EP.a2022.0011","article-title":"Astragaloside IV drug-loaded exosomes (AS-IV EXOs) derived from endothelial progenitor cells improve the viability and tube formation in high-glucose impaired human endothelial cells by promoting miR-214 expression","volume":"73","author":"Zou","year":"2022","journal-title":"Endokrynol. Pol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s10495-019-01582-4","article-title":"MicroRNA-214 targets COX-2 to antagonize indoxyl sulfate (IS)-induced endothelial cell apoptosis","volume":"25","author":"Li","year":"2020","journal-title":"Apoptosis"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Yang, B., Li, S., Zhu, J., Huang, S., Zhang, A., Jia, Z., Ding, G., and Zhang, Y. (2020). miR-214 Protects Against Uric Acid-Induced Endothelial Cell Apoptosis. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00411"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E110","DOI":"10.1152\/ajpendo.00192.2010","article-title":"MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1","volume":"299","author":"Zhao","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1080\/09168451.2017.1364965","article-title":"MicroRNA-34a induces transdifferentiation of glioma stem cells into vascular endothelial cells by targeting Notch pathway","volume":"81","author":"Jin","year":"2017","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1139\/bcb-2018-0304","article-title":"MicroRNA-34a attenuates VEGF-mediated retinal angiogenesis via targeting Notch1","volume":"97","author":"Shi","year":"2019","journal-title":"Biochem. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3404","DOI":"10.1210\/clinem\/dgaa538","article-title":"MicroRNA-15b Targets VEGF and Inhibits Angiogenesis in Proliferative Diabetic Retinopathy","volume":"105","author":"Yang","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5957","DOI":"10.7150\/thno.45422","article-title":"Endothelial cells produce angiocrine factors to regulate bone and cartilage via versatile mechanisms","volume":"10","author":"Zhu","year":"2020","journal-title":"Theranostics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/jcbfm.2010.148","article-title":"Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult","volume":"31","author":"Taboada","year":"2011","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.1016\/j.neuron.2023.09.007","article-title":"Pericytes Control Key Neurovascular Functions and Neuronal Phenotype in the Adult Brain and during Brain Aging","volume":"111","author":"Bell","year":"2023","journal-title":"Neuron"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.devcel.2011.07.001","article-title":"Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises","volume":"21","author":"Armulik","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nature09522","article-title":"Pericytes regulate the blood-brain barrier","volume":"468","author":"Armulik","year":"2010","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nature09513","article-title":"Pericytes are required for blood-brain barrier integrity during embryogenesis","volume":"468","author":"Daneman","year":"2010","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3302","DOI":"10.1161\/STROKEAHA.115.010508","article-title":"Collateral Circulation in Ischemic Stroke: Assessment Tools and Therapeutic Strategies","volume":"46","author":"Bang","year":"2015","journal-title":"Stroke"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"33730","DOI":"10.1109\/ACCESS.2024.3368504","article-title":"Multilevel Multimodal Framework for Automatic Collateral Scoring in Brain Stroke","volume":"12","author":"Raj","year":"2024","journal-title":"IEEE Access"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Maruani, A., Obadia, M., Fontaine, L., Savatovsky, J., Albucher, J.F., Calviere, L., Raposo, N., Cognard, C., Viguier, A., and Albers, G.W. (2024). Hypoperfusion intensity ratio to differentiate between stroke etiologies in patients with a large vessel occlusion. Eur. Stroke J., 23969873241306264.","DOI":"10.1177\/23969873241306264"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"101236","DOI":"10.1016\/j.neurad.2024.101236","article-title":"Impact of cerebral collateral recycle status on clinical outcomes in elderly patients with endovascular stroke treatment","volume":"52","author":"Gong","year":"2025","journal-title":"J. Neuroradiol."},{"key":"ref_70","first-page":"455","article-title":"Vascular endothelial growth factor (VEGF)\u2014Key factor in normal and pathological angiogenesis","volume":"59","author":"Melincovici","year":"2018","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.2174\/1570159X18666200720173316","article-title":"Angiogenesis and Blood-Brain Barrier Permeability in Vascular Remodeling after Stroke","volume":"18","author":"Yang","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4472","DOI":"10.1167\/iovs.10-7061","article-title":"Microvascular retinal endothelial and pericyte cell apoptosis in vitro: Role of hedgehog and Notch signaling","volume":"52","author":"Walshe","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"105953","DOI":"10.1016\/j.neuint.2025.105953","article-title":"Kaempferol promotes angiogenesis through HIF-1\u03b1\/VEGF-A\/Notch1 pathway in ischemic stroke rats","volume":"185","author":"Zhang","year":"2025","journal-title":"Neurochem. Int."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s12264-023-01042-9","article-title":"The Circadian System Is Essential for the Crosstalk of VEGF-Notch-mediated Endothelial Angiogenesis in Ischemic Stroke","volume":"39","author":"Zhang","year":"2023","journal-title":"Neurosci. Bull."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e84493","DOI":"10.7554\/eLife.84493","article-title":"NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice","volume":"12","author":"Zhang","year":"2023","journal-title":"Elife"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41392-023-01704-0","article-title":"Clinical applications of stem cell-derived exosomes","volume":"9","author":"Tan","year":"2024","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/7\/499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:02:05Z","timestamp":1760032925000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/7\/499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":76,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["cimb47070499"],"URL":"https:\/\/doi.org\/10.3390\/cimb47070499","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,1]]}}}