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A. Uemura, Y. Fukushima, S.-I. Nishikawa; Sema3E-PlexinD1 Signaling Facilitates Vascular Regeneration in Ischemic Retina by Selectively Suppressing Disoriented Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3338.
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© ARVO (1962-2015); The Authors (2016-present)
Coordinated actions of various signaling molecules are implicated in determining the angiogenic directions in developing retinas. However it remains unclear what signaling defects are responsible for the disoriented vascular growth in ischemic retinopathies, including diabetic retinopathy and retinopathy of prematurity. To develop a therapeutic modality that guides vascular growth towards ischemic retinas, we assessed the roles of Sema3E and its transmembrane PlexinD1 receptor in developmental and pathological angiogenesis in mouse retinas.
We conducted all the experiments in postnatal mice and oxygen-induced retinopathy (OIR) mouse models with CD1 and C57BL/6 backgrounds. To detect cells expressing the Sema3e and Plxnd1 genes, we performed in situ hybridization in whole-mount retinas. To pharmacologically neutralize endogenous Sema3E ligands, we intravitreally injected soluble PlexinD1 proteins. To genetically mutate Sema3e and Plxnd1 genes, we employed Sema3e-knockout and tamoxifen-inducible Plxnd1-conditional knockout mice, respectively. The retinal vasculature was depicted by whole-mount immunohistochemistry with anti-PECAM-1 and anti-type IV collagen antibodies.
In postnatal mouse retinas, endothelial cells of growing vessels express PlexinD1 whereas underlying neurons in the ganglion cell layer express Sema3E. Disruptions of Sema3E-PlexinD1 signaling evoked ectopic projections of endothelial filopodia, leading to the disorganized formation of retinal vascular networks. In OIR models, while neurons maintain Sema3E expression, PlexinD1 is restrictively expressed in extraretinal vascular tufts. By targeting this PlexinD1, intravitreally injected Sema3E protein selectively prevented extraretinal vascular outgrowth without affecting desirable vascular regeneration in ischemic retinas.
Our study presents not only the roles of Sema3E-PlexinD1 signaling in defining the retinal vascular pathfinding, but also a new paradigm of the vascular regeneration therapy in ischemic retinopathies.
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