Cell cycle regulation of pulmonary vascular remodeling

描述（由申请人提供）：肺动脉高压（PHTN）中的血管重塑是一种异质性疾病，其根据损伤类型而变化，表明血管壁内的平滑肌细胞以不同的方式对不同的刺激作出反应。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肺血管内所有平滑肌细胞的均匀增殖引起的，而是由肺动脉平滑肌细胞（PA SMC）亚群的选择性激活引起的。由于PHTN的原因可能因个体而异，因此了解PA SMC亚型如何对不同类型的损伤做出反应具有潜在的治疗意义。 我们假设，PA SMC的子集，确定其逃避G 0/G1期阻滞血管损伤后的能力，负责PHTN的血管重塑。采用细胞培养、肺外和阻力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剂的体内实验，（p21 Cip 1/Waf 1和p27 Kip 1）缺陷动物，我们将检查：1）在刺激后，与“非增殖性”PA SMC相比，G1细胞周期蛋白在“增殖性”中如何被调节，2）靶向G1期细胞周期蛋白的3种细胞内信号通路的作用（RhoA/Rho激酶、P（3）激酶/AKT和CREB）对调节这些亚型内PA SMC增殖的影响，以及3）三种临床相关疗法的有效性（前列环素、内皮素阻断剂和HMG CoA还原酶抑制剂（他汀类药物））在控制损伤后PA SMC的这些亚组中的增殖中的作用。 我们预计，在这个建议的结论，我们将确定如何选择性地诱导PA SMC的子集增殖，以应对血管损伤。这一信息可能会导致更有针对性的治疗PHTN。

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.