Hypoxic factors in pulmonary hypertension

描述（由申请人提供）：重度肺动脉高压是一种进行性、不可逆的疾病，常因右心衰导致死亡。肺动脉高压的发病机制与包括内皮细胞（内膜重塑）在内的细胞在肺动脉血管壁上的增殖有关，从而导致重塑和肺动脉高压。在重塑过程中涉及的几个因素是由缺氧驱动的。细胞对缺氧作出反应的一种机制是通过稳定缺氧诱导的转录因子（hif）， hif -1 α和hif -2 α。独立研究表明HIF-1alpha和HIF-2alpha都是PH的重要介质。然而，最近的研究报道HIF-2alpha基因位点多态性在适应高海拔的个体中显着增加，这表明HIF-2alpha在PH中起作用。HIF-2alpha独立于HIF-1alpha影响肺血管重塑和PH的机制尚不清楚。本提案的重点是了解HIF-2alpha及其途径在肺动脉高压发病机制中的作用。我们最近发现了一个新的途径，HIF-2alpha- a2a受体途径，通过该途径，HIF-2alpha可以独立于HIF-1alpha促进内皮细胞增殖。我们假设缺氧通过HIF-2alpha和A2A受体依赖机制增加内皮细胞增殖和血管重塑，这是ph发病机制的重要步骤。此外，我们还发现HIF-1alpha独立于HIF-2alpha参与平滑肌细胞增殖。拟议的研究分为三个目的。目的1将利用培养的原代肺内皮细胞和来自高血压大鼠的内皮细胞阐明缺氧和hfs影响内皮细胞生长的机制。第二个目标将用于验证抑制或敲低hif，特别是HIF-2alpha将限制PAH大鼠模型中的血管重塑和PA压力的假设。第三个目的是测试抑制或敲低A2A受体（HIF-2alpha的下游转录靶点）是否可以减轻PAH大鼠模型中的重塑和PA压力。体内目标将研究使用预防模型和拯救模型的效果。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，并为治疗PH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.