Role of Smooth Muscle Progenitor Cells in Obliterative Vascular Remodeling and PH

平滑肌祖细胞在闭塞性血管重塑和 PH 中的作用

基本信息

批准号：
10001625
负责人：
Zhiyu Dai
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001625
关键词：
Address Affect Blood Pressure Blood Vessels CXCL12 gene CXCR4 gene Cell Proliferation Cells Cessation of life Chronic Clinical Complex Data Diphtheria Toxin Disease Distal Endothelial Cells FOXM1 gene Failure Genetic Heart Hypertrophy Heart failure Hypertension Hypoxia Hypoxia Inducible Factor Lead Lesion Lung MYH11 gene Medial Mediating Modeling Morbidity - disease rate Mus Muscle Pathogenesis Patients Pharmacology Phase Phenotype Play Population Procollagen-Proline Dioxygenase Progressive Disease Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Reporter Reporting Research Resistance Role Sampling Signal Transduction Smooth Muscle Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Tamoxifen Thick Treatment Efficacy Vascular Endothelial Cell Vascular remodeling arterial lesion arteriole diphtheria toxin receptor druggable target forkhead protein intima media mortality mouse model new therapeutic target novel premature primary pulmonary hypertension prominin promoter receptor expression stem cells treatment strategy vascular smooth muscle cell proliferation

项目摘要

Pulmonary hypertension (PH) is characterized by obliterative pulmonary vascular remodeling and progressive elevation of pulmonary vascular resistance that leads to right heart failure and eventual death. Although great efforts have been made with known treatment of PH, current therapies fail to reverse the disease and mortality remains high. Better understanding of the pathogenesis of PH is warranty to identify druggable targets for PH patients. Accumulation of smooth muscle cell (SMC) in the intima and media of pulmonary arterial lesion is the hallmark of obliterative pulmonary vascular remodeling. However, the underlying mechanisms remain elusive. Recently, the PI’s previous studies identified a first mouse model of PH [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 PH including idiopathic PAH. Using this model, a subpopulation of smooth muscle progenitor cells expressing CD133 (a marker of progenitor cells) and α-smooth muscle actin (α-SMA) (CD133+ SMPCs) was identified. This population of progenitor cells was enriched at the occlusive vascular lesions as well as the plexiform-like lesions and muscularized pulmonary arterioles. These cells expressed high levels of the proliferation-specific transcription factor Forkhead Box M1 (FoxM1), indicating their highly proliferative potential. Genetic depletion of CD133+ cell population inhibited chronic hypoxia-induced PH. Decreased PH phenotype in another novel mouse model with tamoxifen-inducible deletion of Foxm1 in smooth muscle cells (SMMHC-CreERT2;Foxm1f/f) was also observed. CXCL12 derived from endothelial cells (EC) regulated SMC proliferation and FOXM1 induction. Thus, the proposal hypothesis is that pulmonary vascular ECs and SMPCs cross-talk via CXCL12/CXCR4/FOXM1 signaling plays a fundamental role in mediating obliterative vascular remodeling and thereby severe PH. The proposed studies will address the following Specific Aims. In Aim 1, this study will define the role of the newly identified CD133+ SMPCs in the pathogenesis of obliterative vascular remodeling and severe PH. In Aim 2, this study will address the role of FoxM1 expressed in SMPCs in oblibterative vascular remodeling and severe PH and explore the translational potential of targeting FoxM1. In Aim 3, this study will delineate the integrated signaling responsible for obliterative pulmonary vascular remodeling in CD133+ SMPCs activated by ECs. Completion of these proposed studies will 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 PH in patients.

肺动脉高压（pH）的特征是肺血管重塑和进行性肺血管抗性的升高会导致右心力衰竭和最终死亡。虽然付出了巨大的努力已经通过已知的pH疗法制成，当前的疗法无法扭转疾病，死亡率仍然很高。对pH的发病机理的更好理解是确定pH患者可药物靶标的保证。积累肺部伪像的内膜和培养基中的平滑肌细胞（SMC）是遗忘的标志肺血管重塑。但是，基本机制仍然难以捉摸。最近，Pi的前研究确定了pH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）丙基羟化酶2（PHD2），设计的EGLN1TIE2CRE]，具有渐进性闭塞性血管重塑血管阻塞和丛状病变和正确的心力衰竭，概括了临床pH的许多特征包括特发性PAH。使用此模型，表达CD133的平滑肌祖细胞的亚群（a 鉴定出祖细胞的标记）和α-平滑肌肌动蛋白（α-SMA）（CD133+ SMPC）。这个人口祖细胞在闭塞性血管病变以及丛状病变和肌肉状态富集肺部动物。这些细胞表达了高水平的增殖特异性转录因子叉子盒 M1（FOXM1），表明其高度增殖的潜力。 CD133+细胞种群的遗传部署抑制了慢性缺氧引起的pH。在另一种新型小鼠模型中，pH表型降低，他莫昔佛诱导的缺失的缺失还观察到平滑肌细胞中的FOXM1（SMMHC-CREERT2； FOXM1F/F）。 CXCL12衍生自内皮细胞（EC）调节SMC增殖和FOXM1诱导。那就是提议假设是肺血管ECS SMPC通过CXCL12/CXCR4/FOXM1信号传递在介导闭塞血管中起着基本作用重塑，从而严重pH。拟议的研究将解决以下特定目标。在AIM 1中，这项研究将定义新鉴定的CD133+ SMPC在闭塞性血管重塑和严重的ph。在AIM 2中，这项研究将解决SMPC中表达的FOXM1在固定血管重塑中的作用和严重的pH，并探索靶向FOXM1的翻译潜力。在AIM 3中，这项研究将描述综合的负责在CD133+ SMPC中激活的CD133+ SMPC中闭塞性肺血管重塑的信号传导。完成在这些提出的研究中，将通过阐明的基本机制具有巨大的转化潜力闭塞性血管重塑和识别可以物理倒闭的可药物靶标血管重塑用于治疗患者的严重pH。