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

闭塞性肺血管重塑和严重肺动脉高压的新机制

• 批准号: 9174649
• 负责人: Roberto F. Machado
• 金额: $ 67.96万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174649
• 关键词: Address; Animal Model; Attenuated; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Hypoxia; Cells; Cessation of life; Data; Development; Disease; Endothelial Cells; Exhibits; Functional disorder; Genetic; Goals; Heart failure; Hematopoietic; Human; Hypertrophy; Hypoxia Inducible Factor; Knockout Mice; Lesion; Lung; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Pathogenesis; Patients; Phenotype; Play; Prevention; Procollagen-Proline Dioxygenase; Pulmonary Vascular Resistance; Recruitment Activity; Role; Secondary to; Severities; Signal Transduction; Structure of parenchyma of lung; Systolic Pressure; Tamoxifen; Therapeutic; Vascular Endothelial Cell; Vascular remodeling; Ventricular; abstracting; bHLH-PAS factor HLF; base; clinically relevant; effective therapy; hypoxia inducible factor 1; mortality; mouse model; novel; novel therapeutic intervention; premature; primary pulmonary hypertension; pulmonary arterial hypertension; reconstitution

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

抽象的 肺动脉高压（PAH）的特征是肺部闭塞性血管重塑 肺血管抗性的逐渐增加，导致心力衰竭和过早 死亡。尽管在治疗PAH方面已经取得了长足的进步，但目前的疗法无法逆转 疾病，仅导致发病率和死亡率有所改善。采用小说 带有TIE2CRE介导的EGLN1缺失的小鼠模型[编码缺氧诱导因子（HIF）prolyl 内皮细胞（ECS）和造血细胞中的羟化酶2，PHD2]（EGLN1TIE2小鼠），我们观察到 严重的PAH，右心室收缩压（RVSP）明显升高和严重 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）的患者。这种前所未有的肺血管重塑和 在两种EGLN1的遗传缺失的双突变小鼠中抑制高血压表型 和hif2。我们的支持数据还表明，HIF-2的药物抑制减弱了 EGLN1TIE2小鼠中的PAH表型。有趣的是，WT骨髓移植导致下降 EGLN1TIE2嵌合小鼠中的RVSP和RV肥大，表明骨髓异常 在EGLN1TIE2小鼠中有助于PAH的严重程度。那我们假设EC中的PHD2缺乏症 造血细胞在闭塞血管重塑的发病机理中起着协同作用 通过激活ECS中的HIF-2信号传导和造血细胞中的HIF-1信号传导，严重的PAH。 拟议的研究将解决以下特定目标。在AIM 1中，我们将确定是否 在EGLN1TIE2小鼠中暴露的严重PAH概括了IPAH患者和 定义了继发于PHD2缺乏症继发于介导严重PAH的激活的HIF-2信号的作用。在 AIM 2，我们将解决PHD2缺乏激活的HIF信号在肺中的协同作用 严重PAH机制中的血管EC和造血细胞。 AIM 3的研究将描绘 在EGLN1TIE2小鼠中看到的严重肺血管重塑和由此产生的PAH的分子基础 并探索有选择性靶向HIF-2信号传导以进行预防的翻译潜力和 患者的PAH治疗。鉴于在EGLN1TIE2小鼠中看到的严重PAH明显相似 IPAH患者，我们预计拟议的研究通过识别而具有巨大的翻译潜力 可药物目标和探索可以在药物上进行药物的新型药理剂 抑制/反向血管重塑，以预防和治疗患者的严重PAH。 1