Hypoxic factors in pulmonary hypertension

描述(申请人提供)：重度肺动脉高压是一种进行性不可逆转的疾病，常因右心衰竭而导致死亡。肺动脉高压的发病机制涉及细胞的增殖，包括内皮细胞(内膜重塑)，在肺动脉血管壁上导致重塑和肺动脉高压。参与血管重构过程的几个因素是由缺氧驱动的。细胞对低氧作出反应的一个机制是通过稳定低氧诱导转录因子(HIF)，HIF-1α和HIF-2α。独立研究表明，HIF-1α和HIF-2α在PH中都是重要的介质。然而，最近的研究报道，在适应高海拔地区的个体中，HIF-2α基因座的多态性显著增加，提示HIF-2α在PH中的作用。HIF-2α独立于HIF-1α影响肺血管重塑和肺高压的机制尚不清楚。本研究的重点在于了解HIF-2α在肺动脉高压发病机制中的作用及其途径。我们最近发现了一个新的途径，即HIF-2α-A2A受体途径，通过该途径，HIF-2α可以促进内皮细胞的增殖，而不依赖于HIF-1α。我们假设低氧通过HIF-2α和A2a受体依赖的机制促进内皮细胞增殖和血管重塑，这是PH发病机制中的重要一步。此外，我们还发现HIF-1α参与了平滑肌细胞的增殖，独立于HIF-2α。建议的研究分为三个目标。目的1利用原代培养的肺内皮细胞和高血压大鼠来源的内皮细胞，阐明缺氧和低氧对内皮细胞生长的影响机制。第二个目的将用于验证这样的假设，即抑制或敲除HIF，特别是HIF-2α将限制PAH大鼠模型的血管重塑和PA压力。第三个目标将测试抑制或敲除A2a受体是否可以减轻PAH大鼠模型的重塑和PA压力。A2a受体是HIF-2α的下游转录靶点。体内AIMS将使用预防模型和救援模型来调查效果。这项拟议的研究结果将有助于深入了解影响肺血管重构的缺氧途径，并为PH的治疗提供替代靶点。

DESCRIPTION (provided by applicant): Severe pulmonary hypertension is a progressive and irreversible disease that often leads to mortality due to right heart failure. The pathogenesis of pulmonary hypertension involves proliferation of cells, including endothelial cells (intimal remodeling), in the vessel walls of pulmonary arteries resulting in remodeling and pulmonary hypertension. Several factors implicated in the remodeling process are driven by hypoxia. One mechanism by which cells respond to hypoxia is by stabilization of hypoxia-inducible transcription factors (HIFs), HIF-1alpha and HIF-2alpha. Independent studies suggest that both HIF-1alpha and HIF-2alpha are important mediators in PH. However, recent investigations have reported a marked increase in HIF-2alpha gene locus polymorphism in individuals adapting to high altitudes, suggesting a role of HIF-2alpha in PH. Mechanism by which HIF-2alpha influences pulmonary vascular remodeling and PH, independent of HIF-1alpha is not known. This proposal is focused on understanding the role of HIF-2alpha and its pathways in the pathogenesis of pulmonary hypertension. We have recently identified a new pathway, the HIF-2alpha-A2A receptor pathway, by which HIF-2alpha can promote endothelial proliferation, independent of HIF-1alpha. We hypothesize that hypoxia increases endothelial proliferation and vascular remodeling through a HIF-2alpha and A2A receptor-dependent mechanism and that this is an important step in the pathogenesis of PH. Additionally, we have also identified HIF-1alpha in smooth muscle cell proliferation, independent of HIF-2alpha. The proposed studies are divided into three aims. Aim 1 will elucidate mechanisms by which hypoxia and HIFs influence endothelial growth using cultured primary pulmonary endothelial cells as well as endothelial cells derived from hypertensive rats. The second aim will be used to test the hypothesis that inhibition or knockdown of HIFs, particularly HIF-2alpha will limit vascular remodeling and PA pressures in a rat model of PAH. The third aim will test whether inhibition or knockdown of A2A receptor, a downstream transcriptional target of HIF-2alpha, can mitigate remodeling and PA pressures in a rat model of PAH. The in vivo aims will investigate effects using both a prevention model and a rescue model. Results of the proposed research will help provide insights into hypoxic pathways that influence pulmonary vascular remodeling and offer alternative targets for treatment of PH.