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

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。尽管付出了巨大的努力 虽然已有已知的治疗PH的方法，但目前的治疗方法未能扭转这种疾病，死亡率仍然很高。 更好地了解PH的发病机制是为PH患者确定可用药靶点的保证。积累 肺动脉病变内膜和中层的平滑肌细胞(SMC)异常是闭塞症的标志 肺血管重塑。然而，潜在的机制仍然难以捉摸。最近，私家侦探的前科 研究发现了第一个PH[Tie2Cre-介导的EGLN1干扰小鼠模型，编码低氧诱导因子 (HIF)Pro羟基酶2(PHD2)，命名为Egln1Tie2Cre]与进行性闭塞性血管重塑，包括 血管闭塞和丛状病变和右心衰竭，概括了临床PH的许多特征 包括特发性多环芳烃。使用该模型，表达CD133(A)的一群平滑肌祖细胞 祖细胞标志物)和α-平滑肌肌动蛋白(α-SMA)。这一人口 在闭塞血管病变和丛状病变中，祖细胞丰富且肌肉化。 肺小动脉。这些细胞高水平表达增殖特异性转录因子Forkhead Box M1(FOXM1)，表明它们具有高度的增殖潜力。CD133细胞群体的遗传耗竭抑制了慢性 低氧诱导的PH。他莫昔芬诱导的另一种新型小鼠模型的PH表型降低 血管内皮细胞(SMMHC-CreERT2；Foxm1f/f)表达FOXM1。来源于内皮细胞的CXCL12 (EC)调节SMC增殖和FOXM1的诱导。因此，提出的假设是肺血管内皮细胞 SmPC通过CXCL12/CXCR4/FOXM1信号通路在介导闭塞血管中发挥重要作用 重塑，从而导致严重的肺高压。拟议的研究将涉及以下具体目标。在目标1中，这项研究 将确定新发现的CD133 SMPC在闭塞性血管重塑和 严重的PH值。在目标2中，本研究将探讨SMPC表达的FOXM1在闭塞性血管重塑中的作用。 和严重的PH，并探索靶向FOXM1的翻译潜力。在目标3中，这项研究将勾勒出 内皮细胞激活的CD133 SMPC闭塞性肺血管重构的信号转导。完成 这些拟议的研究中，将有重大的翻译潜力，通过阐明基本机制 闭塞型血管重塑与药物逆转闭塞型药物靶点的确定 血管重塑在重度肺高压患者治疗中的应用

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.