We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.
- Authors
Fukushima, Yoko; Okada, Mitsuhiro; Kataoka, Hiroshi; Hirashima, Masanori; Yoshida, Yutaka; Mann, Fanny; Gomi, Fumi; Nishida, Kohji; Nishikawa, Shin-Ichi; Uemura, Akiyoshi
- Abstract
During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuron-derived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGF-induced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.
- Subjects
ISCHEMIA; RETINA; NEOVASCULARIZATION; BLOOD vessels; HYPEROXIA; GUANOSINE triphosphatase; CELL metabolism; ANIMAL experimentation; HYPOXEMIA; CELLULAR signal transduction; COMPARATIVE studies; EPITHELIAL cells; GLYCOPROTEINS; HYDROLASES; LIGANDS (Biochemistry); RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; NERVE tissue proteins; NEURONS; RESEARCH; RETINAL diseases; EVALUATION research; VASCULAR endothelial growth factors; MEMBRANE glycoproteins; PATHOLOGIC neovascularization; METABOLISM
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 5, p1974
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI44900