Myoendothelial Junction and Microparticle Stimulation of PAH Vascular Lesions

摘要 肺血管闭塞性病变形成的分子机制 动脉高血压(PAH)尚不清楚。正常血管中的PASMC表现为 分化的、收缩的、非增殖的表型。在多环芳烃的发展过程中， PASMC去分化、过度增殖和迁移导致新生内膜 肺小动脉和小动脉闭塞。尽管有几个信号分子 目前尚不清楚导致这种情况的血管信号是什么 去分化和新的内膜病变形成。PAEC和PASMC之间的串扰 长期以来一直被怀疑参与了PAH的发病机制。此外，我们的数据表明，直接 PAECs和PASMCs之间通过肌内皮细胞缝隙连接的相互作用是重要的 以维持正常分化的PASMC表型。受伤或更改 PAEC单层影响相邻PASMCs的分化状态。不仅是因为 PASMC和PAEC相互通信，但PAEC也暴露在许多 循环因素。微粒(MPS)是循环中完整的囊泡，其功能是 调节血管的动态平衡、细胞增殖和血管生成； PAH闭塞血管病变形成。基于这些观察，本提案测试了 整体假说PAECs和PECs之间异常的肌内皮细胞缝隙连接信号 PASMCs通过促进去分化和增殖参与PAH的动脉病变 PAH患者的MPS参与了血管的发病。 通过诱导PAEC功能障碍和干扰缝隙连接信号而导致疾病。特定的 AIMS验证了以下假设：目标1：PAH之间的异常缝隙连接信号 PAECs和PASMCs促进PASMC的脱分化和增殖。目标2：循环 从PAH患者分离的MPS导致PAEC功能障碍并破坏肌内皮细胞间隙 连接信号，导致共培养的PASMCs去分化和增殖。

ABSTRACT 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.