TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth

描述（由申请人提供）：肺动脉高压（PAH）是一种小肺动脉疾病，其特征是肺血管阻力进行性增加，导致右心衰竭并最终死亡。血管收缩和血管舒张之间的失衡以及血管重塑和过度生长是PAH的标志。已知一氧化氮（NO）在PAH中起保护作用，内皮功能衰竭和NO信号转导的丧失有助于人类和实验性PAH。主要研究者最近的工作发现，基质蛋白血小板反应蛋白-1（TSP 1）阻断血管细胞中的生理性NO反应。初步数据表明，TSP 1，在结合其必要的受体CD 47，抑制内皮型一氧化氮合酶（eNOS）的激活，从而内皮NO的生产，和TSP 1和CD 47显着上调人类和实验性PAH。额外的新数据表明，TSP 1-CD 47连接以PDGF依赖性方式刺激PAH中的血管平滑肌细胞过度生长。本提案中待检验的中心假设是，过度TSP 1表达是PAH血管病变的基础，与其同源受体CD 47的相互作用选择性调节与微血管血管反应性、生长和重塑相关的关键第二信使途径。本提案将探讨（i）PAH中TSP 1-CD 47上调背后的机制，（ii）这对血管张力和过度生长的影响，以及（iii）治疗中断关系对预防PAH和改善已建立疾病的影响。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries marked by a progressive increase in pulmonary vascular resistance, leading to right heart failure and ultimately death. An imbalance between vasoconstriction and vasodilation coupled with vascular remodeling and overgrowth are hallmarks of PAH. Nitric oxide (NO) is known to play a protective role in PAH and endothelial failure and loss of NO signaling contribute to both human and experimental PAH. Recent work by the principal investigator has found that the matrix protein thrombospondin-1 (TSP1) blocks physiologic NO responses in vascular cells. Preliminary data suggests that TSP1, in binding to its necessary receptor CD47, inhibits activation of endothelial nitric oxide synthase (eNOS) and thus endothelial NO production, and that TSP1 and CD47 are dramatically upregulated in human and experimental PAH. Additional new data demonstrates that the TSP1-CD47 nexus stimulates vascular smooth muscle cell overgrowth in a PDGF-dependent manner in PAH. The central hypothesis to be tested in this proposal is that excessive TSP1 expression underlies PAH vasculopathy and that interaction with its cognate receptor, CD47, selectively regulates key second messenger pathways linked to microvascular vasoreactivity, growth, and remodeling. The present proposal will explore (i) the mechanisms behind upregulation of TSP1-CD47 in PAH, (ii) the implications this has on vascular tone and overgrowth and (iii) the effects that therapeutic interruption of the nexus has on preventing PAH and on ameliorating established disease.