Defective retinal vascular endothelial cell development as a consequence of impaired integrin αVβ8-mediated activation of transforming growth factor-β.
Defective retinal vascular endothelial cell development as a consequence of impaired integrin αVβ8-mediated activation of transforming growth factor-β.
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DOI：
10.1523/jneurosci.5648-11.2012
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发表时间：
2012-01-25
期刊：
影响因子：
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通讯作者：
Reichardt LF
中科院分区：
文献类型：
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作者：
Arnold TD;Ferrero GM;Qiu H;Phan IT;Akhurst RJ;Huang EJ;Reichardt LF
编码整合素αVβ8（Itgav，Itgb 8）的基因缺失已被证明可导致CNS中血管发育异常，包括产前和围产期出血。其他研究表明，这种整合素在体内的主要功能是促进TGFβ活化。在本文中，我们表明，Itgb 8 mRNA强烈表达在小鼠Müller神经胶质细胞和视网膜神经节细胞，但不是星形胶质细胞。我们进一步表明，Itgb 8在整个视网膜中的缺失严重扰乱了小鼠视网膜血管系统的发育，提高了血管分支点密度和浅表血管丛中的血管覆盖率，同时严重损害了深血管丛的形成。突变血管系统的稳定性也受到损害，如通过出血和缺乏内皮细胞的血管基底层袖的存在所评估的。在Müller神经胶质细胞和神经元中特异性缺失Itgb 8，但在星形胶质细胞中不缺失，重现了在整个视网膜中观察到的Itgb 8后的表型。与αVβ8在TGFβ1活化中的作用一致，我们发现视网膜Tgfb 1缺失导致非常相似的视网膜血管异常。血管缺陷似乎反映了血管内皮细胞中受损的TGFβ信号传导，因为Itgb 8的视网膜缺失减少了内皮细胞中的磷酸化SMAD 3，并且TGFβRII基因的内皮细胞特异性缺失重现了在Itgb 8和TGFβ1突变体中观察到的主要缺陷。特别令人感兴趣的是，在每个突变体中观察到的视网膜血管表型与抑制神经纤毛蛋白-1（先前参与TGFβ活化和信号传导的受体）后的其他突变体的视网膜血管表型显著相似。
Deletions of the genes encoding the integrin αVβ8 (Itgav, Itgb8) have been shown to result in abnormal vascular development in the CNS, including prenatal and perinatal hemorrhage. Other work has indicated that a major function of this integrin in vivo is to promote TGFβ activation. In this paper, we show that Itgb8 mRNA is strongly expressed in murine Müller glia and retinal ganglion cells, but not astrocytes. We further show that Itgb8 deletion in the entire retina severely perturbs development of the murine retinal vasculature, elevating vascular branch point density and vascular coverage in the superficial vascular plexus, while severely impairing formation of the deep vascular plexus. The stability of the mutant vasculature is also impaired as assessed by the presence of hemorrhage and vascular basal lamina sleeves lacking endothelial cells. Specific deletion of Itgb8 in Müller glia and neurons, but not deletion in astrocytes, recapitulates the phenotype observed following Itgb8 in the entire retina. Consistent with αVβ8’s role in TGFβ1 activation, we show that retinal deletion of Tgfb1 results in very similar retinal vascular abnormalities. The vascular deficits appear to reflect impaired TGFβ signaling in vascular endothelial cells because retinal deletion of Itgb8 reduces phospho-SMAD3 in endothelial cells and endothelial cell-specific deletion of the TGFβRII gene recapitulates the major deficits observed in the Itgb8 and TGFβ1 mutants. Of special interest, the retinal vascular phenotypes observed in each mutant are remarkably similar to those of others following inhibition of neuropilin-1, a receptor previously implicated in TGFβ activation and signaling.