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

• 批准号: 9371373
• 负责人: Zhiyu Dai
• 金额: $ 13.26万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371373
• 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; Stem cells; Tamoxifen; Testing; Thick; Treatment Efficacy; Vascular Endothelial Cell; Vascular remodeling; arterial lesion; arteriole; diphtheria toxin receptor; forkhead protein; intima media; mortality; mouse model; new therapeutic target; novel; premature; primary pulmonary hypertension; progenitor; prominin; promoter; receptor expression; treatment strategy; vascular smooth muscle cell proliferation

Title: Role of Smooth Muscle Progenitor Cells in Obliterative Vascular Remodeling and PH Abstract 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, we 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, we identified a subpopulation of smooth muscle progenitor cells expressing CD133 (a marker of progenitor cells) and a-smooth muscle actin (a-SMA) (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 proliferation-specific transcription factor Forkhead Box M1 (FoxM1), indicating their highly proliferative potential. Genetic depletion of CD133+ cell population inhibited chronic hypoxia-induced PH. We also observed decreased PH phenotype in another novel mouse model with tamoxifen-inducible deletion of Foxm1 in smooth muscle cells (SMMHC-CreERT2;Foxm1f/f). We also found that CXCL12 derived from endothelial cells (EC) regulated SMC proliferation and FOXM1 induction. Thus, my 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, we will define the role of the newly identified CD133+ SMPCs in the pathogenesis of obliterative vascular remodeling and severe PH. In Aim 2, we 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, we will delineate the integrated signaling responsible for obliterative pulmonary vascular remodeling in CD133+ SMPCs activated by ECs. 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 PH in patients.

平滑肌前体细胞在闭塞型血管重塑和PH中的作用 摘要 肺动脉高压(PH)的特征是闭塞性肺血管重构和进行性 肺血管阻力升高，导致右心衰竭和最终死亡。虽然很棒 已做出努力治疗肺高压，但目前的治疗方法并不能逆转疾病和死亡率 仍然居高不下。更好地了解PH的发病机制是确定治疗PH的药物靶点的保证 病人。在肺动脉病变的内膜和中层，平滑肌细胞(SMC)的积聚是 闭塞性肺血管重塑的特征。然而，潜在的机制仍然难以捉摸。 最近，我们发现了第一个PH[Tie2Cre]介导的EGLN1干扰的小鼠模型，编码低氧 伴有进行性闭塞血管的诱导因子(HIF)--脯氨酸羟基酶2(PHD2) 重塑包括血管闭塞和丛状病变以及右心衰竭。 包括特发性肺高压在内的许多临床肺高压的特点。使用这个模型，我们确定了Smooth的一个子种群 表达CD133和α-平滑肌肌动蛋白的肌祖细胞 (CD133+SMPC)，在闭塞性血管病变和丛状病变中表达丰富； 肌化的肺小动脉。这些细胞表达高水平的增殖特异性转录。 因子叉头盒M1(FOXM1)，表明其高度增殖潜力。CD133+细胞的遗传耗竭 群体抑制慢性低氧诱导的PH。我们还在另一部小说中观察到PH表型减少 他莫昔芬诱导的血管平滑肌细胞FOXM1缺失的小鼠模型(SMMHC-CreERT2；Foxm1f/f)。 我们还发现内皮细胞来源的CXCL12调节SMC的增殖和FOXM1 归纳法。因此，我的假设是肺血管内皮细胞和平滑肌细胞通过 CXCL12/CXCR4/FOXM1信号通路在介导闭塞性血管重构中发挥重要作用 从而导致严重的PH。拟议的研究将涉及以下具体目标。在目标1中，我们将定义 新发现的CD133+SMPC在闭塞性血管重塑和重度血管重塑发病机制中的作用 pH值在目标2中，我们将探讨SMPC表达的FOXM1在阻塞性血管重塑和 严重的PH并探索靶向FOXM1的翻译潜力。在目标3中，我们将描述集成的 内皮细胞激活的CD133+SMPC闭塞性肺血管重构的信号转导。我们 期望拟议的研究通过阐明基本原理而具有显著的翻译潜力 闭塞性血管重塑的机制及药理作用靶点的确定 逆行闭塞血管重建术治疗重度肺高压