Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension

摘要 肺动脉高压（PAH）的特征是肺部闭塞性血管重塑 以及肺血管阻力的进行性增加，导致右心衰竭和过早死亡。 死亡尽管PAH的治疗已经取得了很大的进步，但目前的治疗方法未能逆转PAH。 疾病，仅导致发病率和死亡率的适度改善。就业小说 Tie 2Cre介导的Egln 1 [编码缺氧诱导因子（HIF）脯氨酰]缺失的小鼠模型 羟化酶2，PHD 2]（Egln 1 Tie 2小鼠）的内皮细胞（EC）和造血细胞，我们观察到， 右心室收缩压（RVSP）显著升高和重度PAH 血管重塑，包括肺血管闭塞和丛状病变，如图所示 特发性PAH（IPAH）患者。这种前所未有的肺血管重塑， 高血压表型在Egln 1基因缺失的双突变小鼠中受到抑制， HIF 2 α我们的支持性数据还表明，药物抑制HIF-2 α可以减弱HIF-1 α的表达， Egln 1 Tie 2小鼠中的PAH表型。有趣的是，WT骨髓移植导致了 Egln 1 Tie 2嵌合体小鼠的RVSP和RV肥大，表明骨髓异常 导致Egln 1 Tie 2小鼠PAH的严重程度。因此，我们假设内皮细胞中的PHD 2缺陷 造血细胞在闭塞性血管重构的发病机制中起协同作用 和严重PAH通过激活内皮细胞中的HIF-2 β信号和造血细胞中的HIF-1 β信号。 拟议的研究将针对以下具体目标。在目标1中，我们将确定 Egln 1 Tie 2小鼠中表现出的重度PAH重现了IPAH患者中PAH的病理生理学， 定义继发于PHD 2缺陷的活化HIF-2 β信号传导在介导重度PAH中的作用。在 目的2，我们将探讨PHD 2缺陷激活的HIF信号在肺动脉粥样硬化中的协同作用。 血管内皮细胞和造血细胞在重度PAH机制中的作用。目标3中的研究将描述 在Egln 1 Tie 2小鼠中观察到的严重肺血管重构和由此产生的PAH的分子基础 并探索选择性靶向HIF-2 α信号转导的翻译潜力， 治疗PAH患者。考虑到在Egln 1 Tie 2小鼠和Egln 1 Tie 2小鼠中观察到的重度PAH的显著相似性， 对于IPAH患者，我们预计拟议的研究具有显著的转化潜力， 药物靶点和探索新的药理学药物， 抑制/逆转血管重塑，用于预防和治疗患者的重度PAH。 1

Abstract Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling in the lungs and progressive increases of pulmonary vascular resistance that cause right heart failure and premature death. Although great strides have been made in treatment of PAH, current therapies fail to reverse the disease and only resulted in a modest improvement in the morbidity and mortality. Employing novel mouse model with Tie2Cre-mediated deletion of Egln1 [encoding hypoxia-inducible factor (HIF) prolyl hydroxylase 2, PHD2] (Egln1Tie2 mice) in endothelial cells (ECs) and hematopoietic cells, we observed severe PAH as evident by markedly elevated right ventricular systolic pressure (RVSP) and severe vascular remodeling including pulmonary vascular occlusion and plexiform-like lesions as seen in patients with idiopathic PAH (IPAH). This unprecedented pulmonary vascular remodeling and hypertensive phenotypes were inhibited in the double mutant mice with genetic deletions of both Egln1 and HIF2. Our Supporting Data also show that pharmacological inhibition of HIF-2 attenuated the PAH phenotype in Egln1Tie2 mice. Intriguingly, WT bone marrow transplantation resulted in decreased RVSP and RV hypertrophy in Egln1Tie2 chimeric mice, indicating that the bone marrow abnormalities contribute to the severity of PAH in Egln1Tie2 mice. Thus, we hypothesize that PHD2 deficiency in ECs and hematopoietic cells plays a synergistic role in the pathogenesis of obliterative vascular remodeling and severe PAH via activation of HIF-2 signaling in ECs and HIF-1 signaling in hematopoietic cells. The proposed studies will address the following Specific Aims. In Aim 1, we will determine whether severe PAH exhibited in Egln1Tie2 mice recapitulates the pathophysiology of PAH in IPAH patients and define the role of activated HIF-2 signaling secondary to PHD2 deficiency in mediating severe PAH. In Aim 2, we will address the synergistic role of PHD2 deficiency-activated HIF signalings in pulmonary vascular ECs and hematopoietic cells in the mechanisms of severe PAH. Studies in Aim 3 will delineate the molecular basis of severe pulmonary vascular remodeling and resultant PAH seen in Egln1Tie2 mice and explore the translational potential of selectively targeting HIF-2 signaling for the prevention and treatment of PAH in patients. Given the marked similarity of severe PAH seen in Egln1Tie2 mice and in IPAH patients, we expect that the proposed studies have significant translational potential by identifying druggable targets and exploring novel pharmacological agents that can pharmacologically inhibit/reverse vascular remodeling for the prevention and treatment of severe PAH in patients. 1