Myoendothelial Junction and Microparticle Stimulation of PAH Vascular Lesions

肌内皮连接和微粒刺激 PAH 血管病变

• 批准号: 8211913
• 负责人: Natalie Norwood Bauer
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211913
• 关键词: Affect; Apoptosis; Apoptotic; Arterial Disorder; Bioenergetics; Biological Markers; Blood Vessels; Caliber; Cell Proliferation; Cells; Coculture Techniques; Communication; Data; Development; Disease; Disease Progression; Endothelin-1; Endothelium; Exhibits; Functional disorder; Gap Junctions; Homeostasis; Hypoxia; Inflammation; Injury; Lesion; Lipids; Lung; Maintenance; Membrane Proteins; Messenger RNA; MicroRNAs; Modeling; Molecular; Outcome; Parents; Pathogenesis; Patients; Phenotype; Process; Property; Proteins; Pulmonary artery structure; Pulmonary vessels; Rattus; Resistance; Role; Serotonin; Severities; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; System; Testing; Therapeutic; Vascular Diseases; Vascular Smooth Muscle; Vesicle; abstracting; angiogenesis; arterial lesion; arteriole; base; hemodynamics; improved; insight; monolayer; novel; novel therapeutics; paracrine; pulmonary arterial hypertension

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)

描述（由申请人提供）： 肺动脉高压（PAH）闭塞性血管病变形成的分子机制尚不清楚。正常血管系统中的PASMC表现出分化的、收缩的、非增殖的表型。在PAH的发展过程中，PASMC去分化并过度增殖和迁移，导致小肺动脉和小动脉的新生内膜闭塞。虽然已经研究了几种信号分子，但仍不清楚导致这种去分化和新生内膜病变形成的血管信号是什么。PAECs和PASMCs之间的相互作用一直被怀疑参与PAH的发病机制。此外，我们的数据表明PAEC和PASMC之间通过肌内皮间隙连接的直接相互作用对于维持正常分化的PASMC表型是重要的。PAEC单层的损伤或改变影响相邻PASMC的分化状态。PASMC和PAEC不仅相互通信，而且PAEC也暴露于许多循环因子。微粒（MP）是循环的完整囊泡，其作为血管稳态、细胞增殖和血管生成的调节剂发挥作用;所有这些都是PAH闭塞性血管病变形成的重要过程。基于这些观察结果，本提案检验了以下总体假设：PAEC和PASMC之间的异常肌内皮间隙连接信号传导通过促进PASMC的去分化和增殖而导致PAH的动脉病，并且来自PAH患者的MP通过诱导PAEC功能障碍和破坏差距连接信号传导而参与血管疾病的发病机制。目的1：PAH PAECs和PASMCs之间异常的缝隙连接信号传导促进PASMCs的去分化和增殖。目标二：从PAH患者分离的循环MP引起PAEC功能障碍并破坏肌内皮间隙连接信号传导，这导致共培养的PASMC的去分化和增殖。 公共卫生相关性：肺动脉高压（PAH）是一种毁灭性疾病，目前治疗有限且无法治愈。这种疾病的特征是在肺血管中形成病变。通过我们提案中的研究，我们希望了解肺血管病变形成的过程，以期开发PAH的新疗法。(End摘要）