Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae
Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae
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DOI：
10.1172/jci64201
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
Nordheim, Alfred
中科院分区：
文献类型：
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作者：
Weinl, Christine;Riehle, Heidemarie;Nordheim, Alfred
视网膜血管内环境稳定确保正常的眼部功能。因此，视网膜血管生成不足和新血管生成，分别导致血管的缺乏和过量，是人类视网膜病理学的标志。我们提供的证据表明，EC特异性基因消融的转录因子SRF或其辅助因子MRTF-A和MRTF-B，但不是SRF辅助因子ELK 1或ELK 4，导致视网膜血管生成不足在出生后的小鼠眼睛。出生后血管生成过程中SRF或MRTF-A/MRTF-B的诱导性EC特异性缺陷会损害内皮尖端细胞丝状伪足突出，导致视网膜初级血管丛形成不完全，缺乏深丛，玻璃体血管持续存在。所有这些特征都是人类血管减少相关的玻璃体视网膜病变的典型特征，例如家族性渗出性玻璃体视网膜病变，包括诺里病。相比之下，成年小鼠血管中Srf的条件性EC缺失引起视网膜内新生血管形成，这让人想起与年龄相关的人类病理学视网膜血管瘤增生和黄斑毛细血管扩张。这些结果表明，血管生成的稳态是由不同的阶段特异性功能的SRF靶基因产物在发展与成熟的视网膜血管系统，并建议肌动蛋白导向的MRTF-SRF信号轴可以作为一个治疗目标，在治疗人类血管视网膜疾病。
Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases.