Mutations in Smooth Muscle Contractile Proteins: Pathways to Vascular Diseases

血管SMCs在动脉中呈多层周向排列，在大的弹性动脉中嵌入弹性蛋白片层之间，或在较小的肌肉动脉中嵌入结缔组织基质。对于收缩功能，SMCs表达平滑肌特异性的α -肌动蛋白和β -肌球蛋白，它们分别聚合形成细和粗纤维。我们已经确定，编码SMC α -肌动蛋白和β -肌球蛋白、ACTA2和MYH11的基因突变，以及控制SMC收缩的激酶、肌球蛋白轻链激酶（MYLK），使个体易患血管疾病，包括胸主动脉瘤、主动脉夹层和闭塞性血管疾病，如早发性冠状动脉疾病和中风。该计划项目资助（PPG）将测试ACTA2、MYH11和MYLK突变导致胸主动脉和疾病和/或闭塞性血管疾病的假设，这是由于SMC对收缩单元功能障碍引起的生物力学应力的不同反应。我们假设这些基因的突变会导致升主动脉中SMC的功能丧失，特别是调节功能丧失或收缩单元的力输出改变，从而导致生物力学应力增加和SMC通路的激活，从而导致胸主动脉瘤和主动脉夹层。相反，我们假设与ACTA2突变子集相关的闭塞性血管疾病，以及可能的MYH11变异，是由肌肉动脉中SMC“功能获得”引起的，特别是由于局灶粘连改变和pdgfr - β受体在异常细胞力产生时的激活而导致SMC增殖增加。来验证这些假设。项目1和2将评估ACTA2和MYH11基因变异对体外动力学、运动性、调控和细丝形成的影响。项目3将评估在ACTA2、MYH11和MYLK突变小鼠模型中，负责血管SMCs血管运动反应性的特定信号模块的年龄依赖性紊乱。项目4将在这些小鼠模型中研究导致胸主动脉疾病和SMC增殖的SMC细胞通路。

Vascular SMCs are arranged circumferentially in arteries in multiple layers, either embedded between layers of elastin lamellae in large elastic arteries or in a matrix of connective tissue in smaller muscular arteries. For contractile function, SMCs express smooth muscle specific isoforms of alpha-actin and Beta-myosin, which multimerize to form thin and thick filaments, respectively. We have determined that mutations in the genes encoding SMC alpha-actin and Beta-myosin, ACTA2 and MYH11, along with the kinase that controls SMC contraction, myosin light chain kinase (MYLK), predispose individuals to vascular diseases, including thoracic aortic aneurysms and aortic dissections and occlusive vascular diseases, such as early onset coronary artery disease and stroke. The Program Project Grant (PPG) will test the hypothesis that the ACTA2, MYH11 and MYLK mutations lead to thoracic aortic and disease and/or occlusive vascular diseases due to a differential SMC response to biomechanical stresses resulting from dysfunction of the contractile unit. We hypothesize that mutations in these genes cause a ¿loss of function¿, specifically loss of regulation or altered force output of contractile unit in SMCs in ascending aorta, resulting in increased biomechanical stresses and activation of SMC pathways leading to thoracic aortic aneurysms and aortic dissections. In contrast, we hypothesize that the occlusive vascular diseases associated with a subset of ACTA2 mutations, and possibly MYH11 variants, result from a SMC "gain of function" in muscular arteries, specifically increased SMC proliferation as a consequence of altered focal adhesions and activation of PDGFR-Beta receptors in response to abnormal cellular force generation. To test these hypotheses. Project 1 and 2 will assess the Impact of ACTA2 and MYH11 genetic variants on kinetics, motility, regulation, and filament formation in vitro. Project 3 will assess age-dependent derangements in specific signaling modules responsible for vasomotor responsiveness in vascular SMCs in mouse models of select ACTA2, MYH11 and MYLK mutations. Project 4 will Investigate SMC cellular pathways leading to thoracic aortic disease and SMC proliferation in these same mouse models.