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）是一种以肺血管阻力进行性增加为特征的小肺动脉疾病，可导致右心衰竭并最终死亡。血管收缩和血管扩张之间的不平衡加上血管重塑和过度生长是PAH的标志。一氧化氮（NO）在多环芳烃中起保护作用，内皮衰竭和NO信号的丢失有助于人类和实验的多环芳烃。最近，首席研究员发现基质蛋白血栓反应蛋白-1 （TSP1）阻断血管细胞的生理性NO反应。初步数据表明，TSP1与其必需受体CD47结合，抑制内皮一氧化氮合酶（eNOS）的激活，从而抑制内皮NO的产生，并且TSP1和CD47在人和实验PAH中显著上调。另外的新数据表明，在PAH中，TSP1-CD47连接以pdgf依赖的方式刺激血管平滑肌细胞过度生长。本研究要验证的中心假设是，过度的TSP1表达是PAH血管病变的基础，其与同源受体CD47的相互作用选择性地调节与微血管反应性、生长和重塑相关的关键第二信使通路。本提案将探讨(i) PAH中TSP1-CD47上调的机制，（ii）这对血管张力和过度生长的影响，以及（iii）治疗性中断联系对预防PAH和改善既定疾病的影响。

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. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a progressive disease that can occur without an identifiable cause or as a consequence of a number of chronic diseases of the lung, heart and liver. In all instances the disease leads to changes in lung function and blood flow that ultimately results in heart failure and death. There are no known cures and available therapy does little to stem the process or extend life. Central to the pathogenesis of PAH is concurrent changes in lung blood vessels that block flow from concurrent increased arterial constriction and thickening of smooth muscle cell layers in small pulmonary arteries. Nitric oxide (NO) is a natural biogas that promotes blood flow and vasodilation in pulmonary blood vessels. Loss of NO signaling is found in PAH and currently useful therapies target NO and try to increase this agent in the lung. Another central mediator of PAH is the smooth muscle cell growth factor platelet derived growth factor (PDGF). We have discovered a novel ligand-receptor interaction between thrombospondin-1 and CD47 that serves as a master regulator of both NO and PDGF. We have also found dramatic upregulation of the TSP1-CD47 nexus in human and several experimental models of PAH. Therapeutics that target the TSP1-CD47 pathway maximize NO and increase blood flow while simultaneously inhibiting smooth muscle cell hypertrophy and arterial thickening. In this proposal we will test the hypothesis that TSP1 promotes PAH through multiple pathways and that blocking TSP1 will both prevent and ameliorate PAH.