整合素信号通路在血管形成中的作用

Vascular malformation is one of the fundamental mechanisms underlying many human diseases. The adapter protein PINCH1 and PINCH2 mediate bidirectional integrin signaling and play important roles in multiple cellular processes and organogenesis. But their roles in vessel formation remain unknown. We generated several endothelial-specific PINCH mutant mouse lines. We found that double deletion of PINCH1 and PINCH2 in endothelial cells led to the absence of endothelial tube formation. Deletion of PINCH1 and one allele of PINCH2 led to a failure of primitive vessel network to remodel and fuse to form large vessels. We hypothesized that PINCH may play important roles in endothelial proliferation, differentiation and migration to form primitive endothelial tubes. High dose of total PINCH expression is required for the recruitment of smooth muscle cells and pericytes to generate mature and functional vessels. To test these, our Specific Aims are: 1) To examine the role of PINCH in endothelial proliferation, differentiation, survival and migration, and ability to form endothelial tubes In Vivo and In Vitro; 2) To examine the role of PINCH in mediating endothelial and mural cell interaction and in vessel wall assembly and maturation; 3) Using candidate gene approach and microarray analysis to investigate molecular mechanisms of PINCH in vascular development. Results of proposed studies will provide novel molecular insights into vessel formation, and will enhance our understanding of the pathology of human disorders associated with vascular malformation.

整合素是细胞外间质蛋白的受体,介导细胞和间质的相互作用。接头蛋白PINCH介导了整合素的双向跨膜信号和多信号通路的整合，在器官发育中起关键作用，但它在血管形成中的作用不明。我们建立了内皮细胞特异性PINCH敲除的小鼠模型。我们发现，双敲除PINCH1和2导致早期血管形成障碍。单敲除PINCH1，或同时杂合敲除PINCH2导致血管成熟和大血管形成障碍。我们推测PINCH调控血管内皮细胞的多种行为和介导血管内皮与周边细胞相互作用。为此，拟开展以下研究：研究PINCH在血管内皮细胞多种行为和血管网形成中的作用；探讨PINCH介导的血管内皮与外周细胞、内皮细胞与间质相互作用在血管的形成、重塑和成熟中的作用；通过对潜在信号通路的研究和基因芯片分析，探索PINCH在血管形成中的分子机制。本研究将阐明血管形成的分子机制并提出新的见解，加深对相关人类疾病发生、发展的理解，为探索更有效的治疗方法提供基础。

整合素是细胞外间质蛋白的受体，介导细胞核间质的相互作用。接头蛋白PINCH介导了整合素的双向跨膜信号和多信号通路的整合，在器官发育中期关键作用。我们建立了内皮细胞特异性PINCH敲除小鼠模型，发现双敲除PINCH1和2导致早期血管形成障碍。单敲除PINCH1，导致血管成熟和大血管形成的障碍。我们阐明了PINCH调控血管内皮细胞的多种行为和介导血管内皮与周边细胞相互作用。我们研究了PINCH在血管内皮细胞多种行为和血管网形成中的作用及PINCH介导的血管内皮与外周细胞，内皮细胞与间质相互作用在血管的形成，重塑和成熟中的作用。我们的研究结果为治疗糖尿病和肿瘤引起的血管病变奠定了理论基础。