Laminin-Dependent Interaction between Astrocytes and Microglia A Role in Retinal Angiogenesis
Laminin-Dependent Interaction between Astrocytes and Microglia A Role in Retinal Angiogenesis
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DOI：
10.1016/j.ajpath.2017.05.016
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发表时间：
2017-09-01
影响因子：
6
通讯作者：
Brunken, William J.
中科院分区：
文献类型：
--
作者：
Biswas, Saptarshi;Bachay, Galina;Brunken, William J.
视网膜血管疾病是后天性失明的主要原因之一。近年来，视网膜小胶质细胞已被证明影响血管分支密度和内皮细胞增殖。然而，在发育过程中小胶质细胞的募集和激活是如何调节的仍不清楚。我们假设小胶质细胞的募集、激活和下游信号传导受壁基底膜成分的调节。我们使用了反向遗传学的方法来破坏层粘连蛋白在血管基底膜的表达，并证明小胶质细胞反应的壁基底膜的亚型特异性的方式。小胶质细胞密度在层粘连蛋白γ 3无效（Lamc 3（-/-））视网膜浅表血管丛中显著增加，因此血管分支密度增加。小胶质细胞也对星形胶质细胞衍生的基质有反应，并且在Lamc 3（-/-）视网膜中或在体外用细胞衍生的基质测试时变得过度活化。野生型视网膜中小胶质细胞的药理学激活产生了Lamc 3（-/-）样血管表型，而Lamc 3（-/-）视网膜中小胶质细胞激活的药理学阻断挽救了野生型血管表型。在分子水平上，Lamc 3（-/-）视网膜中小胶质细胞转化生长因子β 1表达下调，内皮细胞中SMAD信号转导减少，从而增加内皮细胞增殖。在Lamb 2（-/-）视网膜中观察到相反的效果。总之，我们的研究结果证明了一种新的机制，层粘连蛋白调节视网膜血管生成过程中的血管分支和内皮细胞增殖。
Retinal vascular diseases are among the leading causes of acquired blindness. In recent years, retinal microglia have been shown to influence vascular branching density and endothelial cell proliferation. However, how microglial recruitment and activation are regulated during development remains unclear. We hypothesized that microglial recruitment, activation, and down-stream signaling are modulated by components of the mural basement membrane. We used a reverse genetic approach to disrupt laminin expression in the vascular basement membrane and demonstrate that microglia respond to the mural basement membrane in an isoform-specific manner. Microglial density is significantly increased in the Laminin gamma 3 null (Lamc3(-/-)) retinal superficial vascular plexus and consequently the vascular branching density is increased. Microglia also respond to astrocyte-derived matrices and become hyperactivated in the Lamc3(-/-) retina or when tested in vitro with cell-derived matrix. Pharmacological activation of microglia in the wild-type retina produced an Lamc3(-/-)-like vascular phenotype, whereas pharmacological blocking of microglial activation in the Lamc3(-/-) retina rescued the wild-type vascular phenotype. On the molecular level, microglial transforming growth factor-beta 1 expression is down regulated in the Lamc3(-/-) retina, and SMAD signaling decreased in endothelial cells with a consequent increase in endothelial proliferation. The reverse effects were seen in the Lamb2(-/-) retina. Together, our results demonstrate a novel mechanism by which Laminins modulate vascular branching and endothelial cell proliferation during retinal angiogenesis.