Abstract 485: Mitochondrial Complex I Promotes Smooth Muscle Cell Plasticity And Vascular Remodeling

Abstract

Remodeling of the mature vasculature occurs in response to diseases such as atherosclerosis or after vascular injury due to angioplasty or stent placement. Smooth muscle cell (SMC) plasticity is a key factor in this process, but the significance of cellular metabolic and mitochondrial activities in control of SMC plasticity is not well understood. We hypothesized an essential role for mitochondrial respiratory complex I (CI) in SMC proliferation and migration and tested this idea by inactivating the CI subunit NDUFS4 or by using pharmacologic CI inhibitors. In cultured Ndufs4 -/- SMCs, we found lower overall CI expression and activity (P=0.0027), plus decreased respirasome levels, ATP-linked oxygen consumption (P<0.0001), respiratory capacity, NAD + /NADH ratio (P=0.0035), aspartate, and cell proliferation (P<0.0001). NDUFS4 loss increased mitochondrial fragmentation (P<0.0001); interestingly, inhibition of mitochondrial fission restored proliferation of NDUFS4-deficient mouse SMCs and CI inhibitor-treated human SMCs. In addition, loss of NDUFS4 or CI inhibitor treatment limited migration of mouse (P=0.0012) and human (P=0.0022) SMCs, respectively. In vivo , NDUFS4 was highly expressed in the arterial wall during embryogenesis and in cells forming the neointima after arterial injury in adulthood. Mice with embryonic inactivation of SMC Ndufs4 were born in Mendelian ratios, reached adulthood, and lacked an obvious phenotype up to 20 weeks of age; by electron microscopy, however, SMCs in the aortic media revealed altered mitochondrial ultrastructure. To evaluate how SMC CI contributes to arterial injury response in the adult, we inactivated Ndufs4 conditionally at age 6 weeks (NDUFS4 iSMKO) and performed carotid artery ligation; these studies showed that loss of SMC NDUFS4 reduced neointima formation (57% lower intima/media ratio; control, n=13; NDUFS4 iSMKO, n=8; P=0.02). In conclusion, NDUFS4 and thus proper levels of SMC CI are essential for proliferation, migration, normal mitochondrial ultrastructure, and vascular remodeling in adulthood. Mechanistic studies suggest that CI promotes SMC plasticity by supporting biosynthesis of aspartate and ATP, maintaining NAD + /NADH balance, and limiting mitochondrial fragmentation.