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Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice
Yoko Fukushima, … , Shin-Ichi Nishikawa, Akiyoshi Uemura
Yoko Fukushima, … , Shin-Ichi Nishikawa, Akiyoshi Uemura
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):1974-1985. https://doi.org/10.1172/JCI44900.
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Research Article Ophthalmology

Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

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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.

Authors

Yoko Fukushima, Mitsuhiro Okada, Hiroshi Kataoka, Masanori Hirashima, Yutaka Yoshida, Fanny Mann, Fumi Gomi, Kohji Nishida, Shin-Ichi Nishikawa, Akiyoshi Uemura

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Figure 1

ECs express PlexinD1 in response to VEGF signaling in the developing retinal vasculature.

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ECs express PlexinD1 in response to VEGF signaling in the developing ret...
(A) Whole-mount ISH for Vegf in combination with IHC for type IV collagen (Col IV) in the P4 retina. Vegf is expressed in astrocytes ahead of the advancing vessels and around the preformed capillaries and veins, but not around arteries. (B) High-magnification image of the advancing vascular front. Vegf-expressing astrocytes (red) reside adjacent to the tip (arrowhead) and stalk (arrows) ECs (green). (C) ISH for Plxnd1 in combination with IHC for Col IV in the P4 retina. Plxnd1 is expressed in ECs of the developing retinal vasculature, except in arteries. (D) High-magnification image of the advancing vascular front. Plxnd1 (red) is expressed in the tip (arrowheads) and stalk (arrows) ECs (green). (E) ISH for Plxnd1 and IHC for Col IV in P4 retinas 8 hours after intravitreal protein injection. Endothelial Plxnd1 expression is downregulated by VEGFR1-Fc, whereas neuronal Plxnd1 expression is maintained in a dot-like pattern. Note the faint Plxnd1 expression in arteries in the control retina. A, artery; V, vein. Scale bars: 100 μm (A, C, and E); 20 μm (B and D).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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