Metabolic control in vascular remodeling

摘要 血管重塑在胚胎发育和胚胎发育过程中对动脉的形成至关重要。 血管疾病的发病机制，如动脉粥样硬化、再狭窄和移植- 成年期的相关动脉硬化。尽管具有很高的临床意义，但我们的不完整 对血管重塑过程的了解限制了当前能力的发展 预防和治疗策略。血管平滑肌细胞(SMC)是主要的驱动力 发育和成人血管重塑，但SMC活动的机制是 没有完全阐明--特别是线粒体和新陈代谢在这方面的作用 相对未被开发。这项提议的目标是理解基于线粒体的 血管重塑中SMC表型的调节机制。我们已经证明了 FAT1钙粘附素与线粒体呼吸复合体I相互作用并抑制SMC 通过抑制线粒体呼吸而增殖，并反对血管闭塞后 动脉损伤。这些发现表明，呼吸复合体I调节SMC的行为。我们的 新的初步数据进一步支持了这一观点。培养细胞中复合体I亚单位NDUFS4的丢失 SMC降低复合体I水平和活性，限制超复合体的形成 含有复合体I，降低天冬氨酸水平，并损害细胞生长。在体内，NDUFS4高度 在小鼠发育期间，在建造动脉壁的SMC中表达，在成年小鼠中表达 SMC来源的细胞，形成扩张的新生内膜，并因动脉粥样硬化而聚集 受伤。在SMC中选择性缺失NDUFS4的初步研究表明，这些细胞 需要呼吸复合体I才能正常胚胎发育。我们假设这个复合体是 促进SMC在胚胎发育过程中对血管重塑至关重要的活动 成人期。我们将在三个具体目标中测试这个假设，这三个目标分别针对 呼吸复合体功能受损对小鼠SMC关键活动的影响 血管发育，以及3)成人血管动态平衡、损伤和 动脉粥样硬化症。这些研究将增加一个新的基于呼吸复合体的角度-- 易受药物干预--取决于我们对动脉形成和发展的理解 它们如何应对损伤，与组织工程、治疗性血管生成、 肿瘤血管形成和血管疾病。

Summary Vascular remodeling is essential for artery formation during embryogenesis and in the pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant- associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete understanding of the process of vascular remodeling limits current abilities to develop preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of developmental and adult vascular remodeling, but mechanisms underlying SMC activities are not fully elucidated — in particular, the role of mitochondria and metabolism in this context is relatively unexplored. The goal of this proposal is to understand mitochondrion-based mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured SMCs decreases complex I levels and activity, limits the formation of supercomplexes containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly expressed during mouse development in SMCs building the arterial wall, and in adult mice in SMC-derived cells that form the expanding neointima that accumulates in response to arterial injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells require respiratory complex I for normal embryogenesis. We hypothesize that complex I promotes SMC activities important for vascular remodeling during embryogenesis and in adulthood. We will test this hypothesis in three specific aims that respectively address the effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse vascular development, and 3) in models of adult vascular homeostasis, injury, and atherosclerotic disease. These studies will add a new respiratory complex-based angle — susceptible to pharmacological intervention — to our understanding of how arteries form and how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis, tumor vascularization, and vascular disease.