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首页> 外文期刊>The journal of clinical investigation >Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice
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Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

机译：Sema3E-PlexinD1信号传导选择性抑制小鼠缺血性视网膜病中迷失的血管生成

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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.
机译：在发育过程中，视网膜血管以有组织的方式向缺氧区域生长。相比之下，在缺血性视网膜病中，新血管从视网膜表面生长而没有改善视网膜缺氧。恢复适当的血管生成方向性将对缺血性视网膜的复氧和解决疾病的发病机理具有很大的益处。在这里，我们显示信号量3E（Sema3E）配体与跨膜PlexinD1受体的结合启动了一个信号通路，该通路在发育中的视网膜和缺血性视网膜病中均可以正常化血管生成的方向性。在发育中的小鼠视网膜中，VEGF信号转导的抑制导致内皮PlexinD1表达的下调，表明星形胶质细胞衍生的VEGF通常会促进血管生长中PlexinD1的表达。神经元来源的Sema3E向PlexinD1发出信号并激活EC中的小GTPase RhoJ，从而抵消了VEGF引起的丝状伪足投射并确定了视网膜血管寻路。在缺血性视网膜病变的小鼠模型中，视网膜外血管中PlexinD1和RhoJ的表达增强，阻止了VEGF诱导的内皮丝状伪足的脱位投射。值得注意的是，玻璃体内施用Sema3E蛋白可以选择性抑制视网膜外血管的生长，而不会影响所需的视网膜脉管系统再生。我们的研究提出了一种新的血管再生疗法范例，可以将血管生成精确地引导至缺血性视网膜。

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