Myoendothelial Junction and Microparticle Stimulation of PAH Vascular Lesions

描述(由申请人提供)： 肺动脉高压(PAH)闭塞血管病变形成的分子机制尚不清楚。正常血管中的PASMC表现为分化、收缩、非增殖的表型。在PAH的发展过程中，PASMCs去分化、过度增殖和迁移，导致新的小动脉和小动脉内膜闭塞。虽然已经研究了几个信号分子，但目前还不清楚是什么血管信号导致了这种去分化和新的内膜病变的形成。长期以来，PAEC和PASMCs之间的串扰一直被怀疑参与了PAH的发病机制。此外，我们的数据表明，PAEC和PASMC之间通过肌内皮细胞缝隙连接的直接相互作用对于维持正常分化的PASMC表型非常重要。PAEC单层的损伤或改变会影响相邻PASMCs的分化状态。PASMC和PAECs不仅相互沟通，而且PAECs也暴露在众多的循环因素中。微粒(MPS)是循环中完整的囊泡，其功能是调节血管内稳态、细胞增殖和血管生成；这些都是PAH阻塞性血管病变形成的重要过程。基于这些观察结果，本方案验证了以下假设：PAEC和PASMCs之间异常的肌内皮细胞缝隙连接信号通过促进PASMCs的去分化和增殖而参与PAH的动脉病变，而来自PAH患者的MPS通过诱导PAEC功能障碍和干扰缝隙连接信号参与血管疾病的发病。目的1：PAH-PAECs和PASMCs之间异常的缝隙连接信号促进PASMC的脱分化和增殖。目的：从PAH患者分离的循环MPS可引起PAEC功能障碍，干扰肌内皮细胞缝隙连接信号，从而导致共培养的PASMC去分化和增殖。 公共卫生相关性：肺动脉高压(PAH)是一种毁灭性的疾病，目前治疗有限，也没有治愈方法。这种疾病的特点是肺血管内形成病变。通过我们的研究，我们希望了解肺血管病变的形成过程，以期开发治疗PAH的新疗法。(摘要结束)

DESCRIPTION (provided by applicant): The molecular mechanisms underlying formation of occlusive vascular lesions in pulmonary arterial hypertension (PAH) are unknown. PASMCs in the normal vasculature exhibit a differentiated, contractile, non-proliferative phenotype. During the development of PAH, the PASMCs dedifferentiate and become hyperproliferative and migratory leading to neointimal occlusion of small pulmonary arteries and arterioles. Although several signaling molecules have been investigated, it remains unclear what the vascular signals are that cause this dedifferentiation and neointimal lesion formation. Crosstalk between PAECs and PASMCs has long been suspected to participate in pathogenesis of PAH. Further, our data suggest direct interactions between PAECs and PASMCs through myoendothelial gap junctions are important for maintenance of the normal differentiated PASMC phenotype. Injury or alterations to the PAEC monolayer affect the differentiation status of the adjoining PASMCs. Not only do PASMCs and PAECs communicate with each other, but PAECs are also exposed to numerous circulating factors. Microparticles (MPs) are circulating intact vesicles which function as regulators of vascular homeostasis, cell proliferation, and angiogenesis; all vital processes in PAH occlusive vascular lesion formation. Based on these observations this proposal tests the overall hypothesis that aberrant myoendothelial gap junctional signaling between PAECs and PASMCs contributes to the arteriopathy of PAH by promoting dedifferentiation and proliferation of PASMCs, and that MPs from PAH patients participate in the pathogenesis of the vascular disease by inducing PAEC dysfunction and disrupting the gap junctional signaling. Specific Aims test the hypotheses that: Aim 1: Aberrant gap junctional signaling between PAH PAECs and PASMCs promotes PASMC dedifferentiation and proliferation. Aim 2: Circulating MPs isolated from PAH patients cause PAEC dysfunction and disrupt myoendothelial gap junctional signaling, which leads to dedifferentiation and proliferation of co-cultured PASMCs. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a devastating disease for which there is currently limited treatment and no cure. This disease is characterized by lesion formation in the pulmonary vessels. From the studies in our proposal we hope to understand the process for lesion formation in the pulmonary vasculature in the hopes of developing new therapeutics for PAH. (End of Abstract)