(P206) VASCULAR SMOOTH MUSCLE CELL PHENOTYPIC DIFFERENTIATION AND METABOLIC DYSFUNCTION IN THORACIC AORTA ATHEROSCLEROSIS

Background: Changes in vascular smooth muscle cells (vSMC) have proven to be a contributing factor to the development and progression of atherosclerosis. Following arterial injury, vSMCs can undergo differentiation to acquire phenotypes resembling foam cells, mesenchymal stem cells, and osteochondrogenic cells, which can all aid in intimal plaque formation and promote vascular stenosis. Dynamin-related protein 1 (Drp1) is a cytosolic GTPase that mediates mitochondrial fission. Increased mitochondrial fission is affiliated with SMC proliferation and migration, thus increasing the formation of neointimal hyperplasia, forming an anatomical basis for atherosclerosis development. We hypothesize that metabolic (dys)function is critically involved in SMC plasticity. Alterations in mitochondrial morphology and energy production may be affiliated with atherogenic SMC phenotypic switching and remain to be studied.

METHODS AND RESULTS: Mitochondrial dynamics and cellular metabolism were assessed in contractile, synthetic, lipid-loaded, adipogenic, and osteogenic SMCs. To study the role of Drp1 in the development of atherosclerosis, both male and female murine models of atherosclerosis were developed by AAV-mediated proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression and high-fat diet feeding. Via degradation of LDL receptors, PCSK9 upregulation resulted in hyperlipidemia and atherosclerosis. Smooth muscle cell-specific Drp1 knockdown mice and littermate controls were subjected to AAV8-PCSK9 injection and high-fat diet feeding; the development of atherosclerosis was evaluated using murine echocardiography and histological analyses. Sex-specific research questions were generated based on the observations from factorial statistical analysis.

Conclusion: Understanding the metabolic alterations in different SMC phenotypes could be fundamental to finding a therapeutic target to mitigate the pathologic progression of atherosclerosis. We identified the previously undescribed role of Drp1-mediated mitochondrial fission and metabolic changes in vSMC phenotypic differentiation. Additionally, we have initated our investigation analyzing the role of Drp1 in male and female murine models of atherosclerosis.