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: 8335472
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335472
• 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; angiogenesis; arterial lesion; arteriole; base; hemodynamics; improved; insight; monolayer; novel; novel therapeutics; paracrine; pulmonary arterial hypertension

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.

摘要