Sema3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulating endothelial DLL4 and filopodia formation in a rat model of ischemic stroke

Abstract

Angiogenesis is a crucial defense response to hypoxia that regulates the process of raising the promise of long‐term neurologic recovery during the management of stroke. A high expression of antiangiogenic factors leads to the loss of neovascularization capacity in pathologic conditions. We have previously documented an impairment of the cerebral vessel perfusion and neovascularization in the cortex neighboring the stroke‐induced lesion, which was accompanied by an activation of semaphorin 3E (Sema3E)/PlexinD1 after ischemic stroke. In this study, we employed micro‐optical sectioning tomography to fully investigate the details of the vascular pattern, including the capillaries. We found that after transient middle cerebral artery occlusion, inhibiting PlexinD1 signaling led to an organized recovery of the vascular network in the ischemic area. We then further explored the possible mechanisms. In vivo, Sema3E substantially decreased dynamic delta‐like 4 (DLL4) expression. In cultured brain microvascular endothelial cells, Sema3E down‐regulated DLL4 expression via inhibiting Ras‐related C3 botulinum toxin substrate 1–induced JNK phosphorylation. At the microcosmic level, Sema3E/PlexinD1 signaling promoted F‐actin disassembly and focal adhesion reduction by activating the small guanosine triphosphatase Ras homolog family member J by releasing RhoGEF Tuba from direct binding to PlexinD1, thus mediating endothelial cell motility and filopodia retraction. Our study reveals that Sema3E/PlexinD1 signaling, which suppressed endothelial DLL4 expression, cell motility, and filopodia formation, is expected to be a novel druggable target for angiogenesis during poststroke progression.— Zhou, Y.‐F., Chen, A.‐Q., Wu, J.‐H., Mao, L., Xia, Y.‐P., Jin, H.‐J., He, Q.‐W., Miao, Q. R., Yue, Z.‐Y., Liu, X.‐L., Huang, M., Li, Y.‐N., Hu, B. Sema3E/PlexinD1 signaling inhibits postischemic angiogenesis by regulating endothelial DLL4 and filopodia formation in a rat model of ischemic stroke. FASEB J. 33, 4947–4961 (2019). http://www.fasebj.org

pH‐Sensitive, Cerebral Vasculature‐Targeting Hydroxyethyl Starch Functionalized Nanoparticles for Improved Angiogenesis and Neurological Function Recovery in Ischemic Stroke

“…The percentage volume loss was calculated as (contralateral hemispheric volume – Ipsilateral hemispheric volume)/(contralateral hemisphere volume) × 100%. [ 50 ]…”

Insights into the regulatory role of Plexin D1 signalling in cardiovascular development and diseases

“…Recently, many studies have reported the emerging effects of PLXND1 in the cardiovascular system 27,[35][36][37] ; particularly, a study by Ellie Tzima and colleagues described that PLXND1 functions as an endothelial mechanosensor and regulates vascular function and the site-specific distribution of atherosclerosis. 35 This finding suggests that a systematic summary of the emerging role of PLXND1 in cardiovascular development and disease, as well as the possible molecular mechanisms, is urgently needed.…”

“…100 Angiogenesis is a crucial defence against hypoxia and regulates the process of long-term neurologic recovery during the management of stroke. 36 The model of vessel sprouting demonstrated that new branches in angiogenesis were spearheaded by tip cells. 101 Only high expression of DLL4 in ECs determines tip cell selection.…”

“…The increased RhoJ activity leads to F-actin disassembly and focal adhesion reduction. 36 Moreover, SEMA3E-PLXND1 inhibits DLL4 expression by inactivating the Rac1-JNK signalling pathway under oxygen-glucose deprivation and reoxygenation (OGDR) conditions. 36 This finding suggests that inhibiting SEMA3E-PLXND1 signalling is a novel therapeutic strategy for improving brain tissue survival and functional recovery after ischaemic stroke.…”

Semaphorins in Angiogenesis and Autoimmune Diseases: Therapeutic Targets?

“…Studies with Sema 3E −/− mice revealed the important role that avascular zones generated by Sema3E play in guiding cardiac vessel development (48). Further, in a rat model of ischemic stroke, it was shown that Sema3E/Plexin-D1 signaling inhibited angiogenesis through regulation of endothelial dynamic deltalike 4 molecule (64).…”