Vascular remodeling is essential for artery formation during embryogenesis and their response to injury or vascular disease (e.g., atherosclerosis) in adulthood. Despite this clinical significance, incomplete grasp of vascular remodeling limits 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 FAT1 cadherin interacts with and inhibits 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 preliminary data further support this idea. Loss of complex I subunit NDUFS4 in SMCs decreases complex I levels and activity, formation of supercomplexes containing complex I, aspartate levels, and 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 in the expanding neointima induced by arterial injury. Notably, we used conditional gene inactivation in mice to delete NDUFS4 selectively in SMCs, and in postnatal screening, found a lower than expected frequency of SMC-NDUFS4-deficient animals, suggesting that SMCs require respiratory complex I for normal embryogenesis. We hypothesize that mitochondrial complex I promotes SMC activities important for vascular remodeling during embryogenesis and in adulthood, and will test this hypothesis in three specific aims: Aim 1 Evaluate the role of mitochondrial complex I in SMC proliferation, survival, migration/invasion and differentiation, and determine underlying mechanisms. Aim 2 Determine the significance of mitochondrial complex I in SMCs during artery formation. Aim 3 Define the role of mitochondrial complex I in SMCs in vascular homeostasis and in the response to vascular injury in adulthood. This study 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.
|Program type||Career Development Award|
|Effective start/end date||04/01/2019 → 03/31/2022|