Targeting Smooth Muscle Progenitor Cells for Treatment of Pulmonary Arterial Hypertension

靶向平滑肌祖细胞治疗肺动脉高压

• 批准号: 10189689
• 负责人: YOU-YANG ZHAO
• 金额: $ 49.73万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189689
• 关键词: Address; Angiogenic Factor; Animal Model; Attenuated; Blood Pressure; Blood Vessels; CXCL12 gene; CXCR4 gene; Cell Cycle; Cells; Cessation of life; Chronic; Clinical; Data; Diphtheria Toxin; Disease; Distal; Endothelial Cells; Endothelium; FOXM1 gene; Genetic; Heart Hypertrophy; Heart failure; Hypertension; Hypoxia; Hypoxia Inducible Factor; Lead; Lesion; Lung; Lung diseases; Mediating; Modeling; Molecular; Monocrotaline; Mus; Muscle; Muscle satellite cell; Pathogenesis; Pathologic; Patients; Pharmacology; Play; Population; Procollagen-Proline Dioxygenase; Pulmonary Vascular Resistance; Rattus; Reporter; Reporting; Resistance; Role; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Structure of parenchyma of lung; Tamoxifen; Testing; Therapeutic; Thiostrepton; Tissues; Vascular remodeling; adenoviral-mediated; alpha Actin; arterial lesion; arteriole; diphtheria toxin receptor; druggable target; effective therapy; forkhead protein; inhibitor/antagonist; intima media; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; premature; primary pulmonary hypertension; progenitor; prominin; promoter; pulmonary arterial hypertension; receptor expression; recombinant adenovirus; stem cells

Pulmonary arterial hypertension (PAH) is characterized by obliterative pulmonary vascular remodeling and progressive elevation of pulmonary vascular resistance that leads to right heart failure and premature death. Although great efforts have been made to treat PAH, current therapies fail to reverse the disease and mortality remains high. Comprehensive understanding of the mechanisms underlying obliterative pulmonary vascular remodeling is warranted to identify druggable targets for effective treatment of PAH. Accumulation of smooth muscle cell (SMC) in the pulmonary vascular lesions is the hallmark of obliterative pulmonary vascular remodeling. We have recently identified the first mouse model of PAH [Tie2Cre-mediated disruption of Egln1, encoding hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2), designated Egln1Tie2Cre] with progressive obliterative vascular remodeling including vascular occlusion and plexiform-like lesion, and right heart failure, which recapitulates many features of clinical PAH. Using this mouse model as well as the Sugen/Hypoxia rat model, we identified a subpopulation of smooth muscle progenitor cells expressing CD133 (a marker of progenitor cells) (CD133+ SMPCs) which were enriched at the occlusive vascular lesions as well as the plexiform-like lesions and muscularized pulmonary arterioles. These cells expressed high levels of the cell cycle master regulator Forkhead Box M1 (FoxM1), indicating the highly proliferative potential. Genetic depletion of CD133+ cell population inhibited chronic hypoxia-induced PH. We also observed decreased vascular remodeling and PH in mice with tamoxifen-inducible deletion of Foxm1 in smooth muscle cells. Pharmacological inhibition of FoxM1 attenuated PAH in Sugen/Hypoxia-exposed rats. Thus, we hypothesize that EC-SMPC crosstalk regulates CD133+ SMPC proliferation in a FoxM1-dependent manner and thereby plays a fundamental role in the mechanisms of obliterative vascular remodeling and severe PAH. The proposed studies will address the following Specific Aims. In Aim 1, we will determine the role of smooth muscle progenitor cells in the mechanisms of pulmonary vascular remodeling and PAH. In Aim 2, we will delineate the molecular mechanisms of SMPC-mediated vascular remodeling in PAH. In Aim 3, we will explore the translational potential of targeting FoxM1 for treatment of PAH. We expect that the proposed studies have significant translational potential by elucidating the fundamental mechanisms of obliterative vascular remodeling and identifying druggable targets that can pharmacologically reverse obliterative vascular remodeling for the treatment of severe PAH in patients.

肺动脉高压（PAH）的特征是肺血管重塑和 肺血管抗性的逐渐升高会导致右心力衰竭和过早死亡。 尽管已经为治疗PAH做出了巨大的努力，但目前的疗法无法扭转疾病和死亡率 保持高。对牙科肺血管的基础机制的全面理解 有必要进行重塑以确定有效治疗PAH的可药靶标。光滑的积累 肺血管病变中的肌肉细胞（SMC）是闭塞性肺血管的标志 重塑。我们最近确定了PAH的第一个小鼠模型[TIE2CRE介导的EGLN1的破坏， 编码缺氧诱导因子（HIF）丙酰羟化酶2（PHD2），指定为EGLN1TIE2CRE] 闭塞性血管重塑，包括血管闭塞和丛状病变和右心衰竭， 这概括了临床PAH的许多特征。使用此鼠标模型以及Sugen/缺氧大鼠 模型，我们确定了表达CD133的平滑肌祖细胞的亚群（ 祖细胞（CD133+ SMPC），在闭塞性血管病变上富含 丛状的病变和肌肉发达的肺动脉。这些细胞表达了高水平的细胞周期 主调节器叉子盒M1（FOXM1），表明具有高度增殖的潜力。遗传耗竭 CD133+细胞种群抑制了慢性缺氧诱导的pH值。我们还观察到血管重塑减少 在平滑肌细胞中使用他莫昔芬可诱导的FOXM1缺失的小鼠和pH值。药理抑制 FOXM1在Sugen/低氧大鼠中减弱了PAH。因此，我们假设EC-SMPC串扰 以FoxM1依赖性方式调节CD133+ SMPC增殖，从而在 闭塞血管重塑和严重PAH的机制。拟议的研究将解决 遵循特定目标。在AIM 1中，我们将确定平滑肌祖细胞在 肺血管重塑和PAH的机制。在AIM 2中，我们将描述分子机制 PAH中SMPC介导的血管重塑。在AIM 3中，我们将探索定位的翻译潜力 FOXM1治疗PAH。我们预计拟议的研究具有巨大的翻译潜力 阐明闭塞血管重塑的基本机制并识别可药物的目标 这可以在药理上逆转闭塞性血管重塑，以治疗患者的严重PAH。

项目成果

Loss of Endothelial Hypoxia Inducible Factor-Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis.

• DOI: 10.1161/jaha.121.022077
• 发表时间: 2021-11-16
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Dai Z;Cheng J;Liu B;Yi D;Feng A;Wang T;An L;Gao C;Wang Y;Zhu MM;Zhang X;Zhao YY
• 通讯作者: Zhao YY

TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury.

• DOI: 10.1152/ajplung.00226.2021
• 发表时间: 2021-08
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: K. Su;Lulong Bo;Chunling Jiang;Xiaoming Deng;Y. Zhao;R. Minshall;G. Hu

Endothelial PHD2 deficiency induces nitrative stress via suppression of caveolin-1 in pulmonary hypertension.

• DOI: 10.1183/13993003.02643-2021
• 发表时间: 2022-12
• 期刊: The European respiratory journal

Endothelial cells in the pathogenesis of pulmonary arterial hypertension.

• DOI: 10.1183/13993003.03957-2020
• 发表时间: 2021-09
• 期刊: The European respiratory journal
• 作者: Evans CE;Cober ND;Dai Z;Stewart DJ;Zhao YY
• 通讯作者: Zhao YY

Suppression of BMP signaling by PHD2 deficiency in Pulmonary Arterial hypertension.

• DOI: 10.1002/pul2.12056
• 发表时间: 2022-01
• 期刊: PULMONARY CIRCULATION
• 影响因子: 2.6
• 作者: Liu, Bin;Yi, Dan;Pan, Jiakai;Dai, Jingbo;Zhu, Maggie M.;Zhao, You-Yang;Oh, S. Paul;Fallon, Michael B.;Dai, Zhiyu
• 通讯作者: Dai, Zhiyu