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

肺动脉高压（PH）是以闭塞性肺血管重构和进行性肺动脉高压为特征的一种肺动脉高压。 肺血管阻力升高，导致右心衰竭并最终死亡。虽然付出了巨大的努力 虽然已经用已知的PH治疗方法进行了研究，但目前的治疗方法未能逆转该疾病，死亡率仍然很高。 深入了解PH的发病机制是确定PH治疗靶点的保证。积累 肺动脉内膜和中膜平滑肌细胞（smooth muscle cell，SMC）的大量增殖是肺动脉闭塞性病变的标志 肺血管重构然而，根本的机制仍然难以捉摸。最近，PI的前 研究确定了第一个PH [Tie 2Cre]介导的Egln 1（编码缺氧诱导因子）破坏的小鼠模型 (HIF)脯氨酰羟化酶2（PHD 2），命名为Egln 1 Tie 2Cre]，伴有进行性闭塞性血管重塑，包括 血管闭塞和丛状病变以及右心衰竭，这概括了临床PH的许多特征 包括特发性肺动脉高压使用该模型，表达CD 133的平滑肌祖细胞亚群（a 祖细胞标志物）和α-平滑肌肌动蛋白（α-SMA）（CD 133 + SMPCs）。这一人口 祖细胞在闭塞性血管病变以及丛状病变处富集， 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（FoxM 1），表明其高度增殖潜力。CD 133+细胞群体的遗传耗竭抑制慢性 在另一种新的具有他莫昔芬诱导的缺失的小鼠模型中， 还观察到平滑肌细胞（SMMHC-CreERT 2; Foxm 1f/f）中的Foxm 1。来源于内皮细胞的CXCL 12 (EC)调节SMC增殖和FOXM 1诱导。因此，提出的假设是，肺血管内皮细胞 通过CXCL 12/CXCR 4/FOXM 1信号转导的SMPC串扰在介导闭塞性血管病变中起着重要作用。 重塑，从而严重PH。拟议的研究将解决以下具体目标。在第一项研究中， 将确定新鉴定的CD 133 + SMPC在闭塞性血管重塑发病机制中的作用， 在目的2中，本研究将探讨SMPC中表达的FoxM 1在闭塞性血管重塑中的作用 和重度PH，并探索靶向FoxM 1的翻译潜力。在目标3中，本研究将描述综合的 在EC激活的CD 133 + SMPC中负责闭塞性肺血管重塑的信号传导。完成 这些拟议的研究将有显着的翻译潜力，阐明的基本机制， 闭塞性血管重塑和确定可逆转闭塞性血管重塑的药物靶点。 血管重塑用于治疗重度PH患者。

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.