EMBO Molecular Medicine | |
Semaphorin‐3C signals through Neuropilin‐1 and PlexinD1 receptors to inhibit pathological angiogenesis | |
Wan-Jen Yang2  Junhao Hu3  Akiyoshi Uemura4  Fabian Tetzlaff2  Hellmut G Augustin1  | |
[1] Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM), Heidelberg University, Mannheim, Germany;Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany;Vascular Oncology and Metastasis (A190), German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany;Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan | |
关键词: angiogenesis; semaphorin; retinopathy of prematurity; Sema3C; | |
DOI : 10.15252/emmm.201404922 | |
来源: Wiley | |
【 摘 要 】
Retinopathy of prematurity causes visual impairment due to destructive neoangiogenesis after degeneration of the retinal microvasculature. This study was aimed at analyzing whether local delivery of Semaphorin-3C (Sema3C) suppresses pathological retinal angiogenesis. Sema3C exerted potent inhibiting effects in cellular models of angiogenesis. In an endothelial cell xenotransplantation assay, Sema3C acted primarily on immature microvessels by inducing endothelial cell apoptosis. Intravitreal administration of recombinant Sema3C disrupted endothelial tip cell formation and cell–cell contacts, which led to decreased vascular bed expansion and vessel branching in the growing retinal vasculature of newborn mice, while not affecting mature vessels in the adult retina. Sema3C administration strongly inhibited the formation of pathological pre-retinal vascular tufts during oxygen-induced retinopathy. Mechanistically, Sema3C signaled through the receptors Neuropilin-1 and PlexinD1, which were strongly expressed on vascular tufts, induced VE-cadherin internalization, and abrogated vascular endothelial growth factor (VEGF)-induced activation of the kinases AKT, FAK, and p38MAPK. This disrupted endothelial cell junctions, focal adhesions, and cytoskeleton assembly resulted in decreased cell migration and survival. Thus, this study identified Sema3C as a potent and selective inhibitor of pathological retinal angiogenesis. Semaphorin-3C is a potent and selective inhibitor of pathological retinal angiogenesis that acts by signaling through Nrp-1 and PlexinD1 receptors.Abstract
Synopsis
【 授权许可】
CC BY
© 2015 The Authors. Published under the terms of the CC BY 4.0 license
Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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