Cell cycle regulation of pulmonary vascular remodeling

描述(申请人提供)：肺动脉高压(PHTN)的血管重构是一种异质性疾病，根据损伤类型的不同而不同，这表明血管壁中的平滑肌细胞以不同的方式对不同的刺激做出反应。我们的初步数据表明，与PHTN相关的中膜增厚和血管重塑并不是由于肺血管内所有平滑肌细胞的均匀增殖，而是由于选择性地激活了肺动脉平滑肌细胞(PA SMC)的亚群。由于PHTN的病因因人而异，了解不同类型的PA SMC对不同类型的损伤的反应具有潜在的治疗意义。 我们推测，PA SMC的亚群在血管损伤后逃脱G0/G1期停滞的能力，是PHTN血管重塑的主要原因。通过细胞培养、叶外和阻力肺血管器官培养，以及野生型和细胞周期蛋白依赖性激酶抑制物(p21Cip1/Waf1和p27Kip1)缺陷动物的体内实验，我们将研究：1)与非增殖性PA SMC相比，G1细胞周期蛋白在刺激后如何被调节；2)针对G1细胞周期蛋白的3条细胞内信号通路(RhoA/Rho激酶、P(3)K/AKT和CREB)在调节这些亚型中PA SMC增殖中的作用；3)三种临床相关疗法(前列环素、内毒素阻滞剂、CREB)的有效性和HMG CoA还原酶抑制剂(他汀类药物)，以控制损伤后PA SMC的这些亚群(S)的增殖。 我们预计，在本提案的结论中，我们将确定PA SMC亚群是如何选择性地诱导增殖以响应血管损伤的。这一信息可能会导致对PHTN的更有针对性的治疗。

DESCRIPTION (provided by applicant): Vascular remodeling in pulmonary arterial hypertension (PHTN) is a heterogeneous disorder which varies depending upon the type of injury, suggesting that smooth muscle cells within a vessel wall respond in distinct ways to different stimuli. Our preliminary data suggests that the medial thickening and vascular remodeling associated with PHTN does not result from a uniform proliferation of all smooth muscle cells within the pulmonary vessel, but from selective activation of subsets of pulmonary artery smooth muscle cells (PA SMC). Since the cause of PHTN can vary between individuals, understanding how subtypes of PA SMC respond to different types of injury has potential therapeutic implication. We hypothesize that subsets of PA SMC, identified by their ability to escape G0/G1 arrest following vascular injury, are responsible for the vessel remodeling in PHTN. Using cell culture, organ culture of extra-lobar and resistance pulmonary vessels, and in vivo experiments from both wild type and cyclin-dependent kinase inhibitor- (p21Cip1/Waf1 and p27Kip1) deficient animals we will examine: 1) how G1 cell cycle proteins are regulated in 'proliferative' compared to 'non-proliferative' PA SMC following stimulation, 2) the role of 3 intracellular signaling pathways which target G1 cell cycle proteins (RhoA/Rho kinase, P(3) kinase/AKT, and CREB) on regulating PA SMC proliferation within these subtypes, and 3) the effectiveness of three clinically relevant therapies (prostacyclin, endothelin blockers, and HMG CoA reductase inhibitors (statins)) in controlling proliferation in these subset(s) of PA SMC following injury. We anticipate that at the conclusion of this proposal we will have identified how subsets of PA SMC are selectively induced to proliferate in response to vascular injury. This information may lead to more targeted therapy for the treatment of PHTN.