Pathological arterial muscularization and the role of integrins

病理性动脉肌化和整合素的作用

• 批准号: 8969702
• 负责人: Daniel Greif
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-17 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969702
• 关键词: Actins; Adhesions; Aorta; Aortic Valve Stenosis; Arterial Disorder; Arterial Medias; Arteries; Atherosclerosis; Attenuated; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Cell Differentiation process; Cell Proliferation; Cells; Cytoskeleton; Disease; Distal; Down-Regulation; Elastin; Embryo; Endothelial Cells; Extracellular Matrix; Gene Dosage; Genes; Genetic; Goals; Growth; Health; Homeobox; Human; Injury; Integrin beta3; Integrins; Intervention; Knockout Mice; Link; Longevity; Lung; Maps; Mediating; Mitogens; Modeling; Molecular; Mus; Mutant Strains Mice; Operative Surgical Procedures; Pathogenesis; Pathology; Pericytes; Phenotype; Plague; Population; Pulmonary Hypertension; Regulation; Role; Series; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Stenosis; Stimulus; Sum; Supravalvular aortic stenosis; Testing; Tissues; Transgenic Organisms; Tunica Media; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Work; arteriole; cell motility; combat; dosage; effective therapy; human disease; in vivo; induced pluripotent stem cell; injured; loss of function mutation; migration; mouse model; mutant; novel; novel therapeutics; null mutation; overexpression; postnatal; prevent; pup; receptor; response; restenosis; transcription factor

DESCRIPTION (provided by applicant): Cardiovascular diseases exert a massive burden on human health, and our long term objective is to attenuate the excessive accumulation of vascular smooth muscle cells (VSMCs) that is central to many of these diseases. The tunica media of the normal artery is composed of alternating circumferential layers of VSMCs and elastic lamellae. Diverse arterial disorders, including atherosclerosis, restenosis, pulmonary hypertension and supravalvular aortic stenosis (SVAS) are plagued by defective elastic lamellae as well as hypermuscularization. SVAS, a devastating human disease characterized by an increased VSMC burden that occludes large arteries, is caused by heterozygous null mutations in the elastin gene ELN. Similarly, elastin mutant mice develop hypermuscularization and stenosis of large arteries, such as the aorta. Major vascular surgery is the only current treatment for SVAS as no effective pharmacological options are available. A major obstacle to developing effective therapies for vascular disorders is the poor understanding of the cellular source(s) of excess VSMCs; indeed no prior studies have traced the lineage of any cell populations in elastin mutants. In addition, the molecular and cellular mechanisms underlying aortic hypermuscularization in elastin mutants are not well defined. Our initial studies indicate that integrin �expression and integrin signaling is robustly upregulated in the elastin mutant aorta and that reduction of �levels or activity attenuates the excessive muscularization. Furthermore, reduction of the dosage of the gene encoding � Itgb3, extends the viability of Eln(-/-) pups which is unprecedented for any genetic or pharmacological intervention. A potentially attractive strategy for reducing arterial hypermuscularization in SVAS is attenuating the increased �expression. Although little is known regarding regulation of �expression, the growth arrest-specific homeobox (Gax) transcription factor is expressed in VSMCs and Gax overexpression reduces �levels, proliferation and migration. We hypothesize that in elastin mutants, Gax downregulation induces integrin �expression in pre-existing aortic smooth muscle resulting in aberrant VSMC orientation, proliferation and migration and thus aortic stenosis. This proposal utilizes studies of transgenic mutant mice, VSMCs isolated from the murine aorta and human SVAS aortic tissue and cells to test this hypothesis in three specific aims: 1) in the elastin mutant aorta, identify the cellular source(s) of excessive VSMCs; 2) in elastin deficient mice, murine VSMCs and human SVAS-derived smooth muscle cells, elucidate the molecular and cellular mechanisms underlying integrin �induced excess aortic muscularization; and 3) elucidate the role of Gax in mediating enhanced integrin �expression and hypermuscularization in elastin mutants. Taken together, our proposed studies will delineate mechanisms underlying the identified link between elastin deficiency, integrin �and aortic hypermuscularization and thereby provide concrete steps towards developing novel therapeutic strategies for SVAS and other vasculoproliferative diseases.

描述（由申请人提供）：心血管疾病对人类健康造成巨大负担，我们的长期目标是减轻血管平滑肌细胞（VSMCs）的过度积累，这是许多这些疾病的核心。正常动脉的中膜由VSMCs的周向层和弹性片层交替组成。多种动脉疾病，包括动脉粥样硬化、再狭窄、肺动脉高压和瓣上主动脉狭窄（SVAS），都是由弹性瓣片缺陷和肌肉肥大所困扰的。SVAS是一种破坏性的人类疾病，其特征是VSMC负担增加，阻塞大动脉，是由弹性蛋白基因ELN的杂合零突变引起的。同样，弹性蛋白突变小鼠也会出现肌肉肥大和大动脉（如主动脉）狭窄。大血管手术是目前唯一的治疗方法