Metabolic control of vascular smooth muscle cell plasticity

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The dedifferentiation of vascular smooth muscle cells (SMCs) into synthetic SMCs, a hallmark of many occlusive vascular diseases, is associated with a metabolic switch that is characterized by increased aerobic glycolysis, which also fuels mevalonate metabolism, decreased glucose oxidation and increased fatty acid oxidation. However, the molecular links between environmental cues and the metabolic reprogramming remain poorly understood. Our pilot studies revealed that cyclin dependent kinase 8 (CDK8) is a master regulator of the metabolic control of vascular SMC dedifferentiation for intimal hyperplasia toward vascular occlusion. Mechanistic investigations uncovered that CDK8 controls the SREBP2 (sterol regulatory element binding factor-2)-operated transcription to promote the mevalonate metabolism for protein geranylgeranylation, which drives the vascular SMC dedifferentiation. Thus, we propose a novel paradigm in which CDK8 controls the mevalonate metabolism for protein geranylgeranylation to promote the dedifferentiation of vascular SMCs for intimal hyperplasia, thereby contributing to occlusive vascular disease. We will test this hypothesis and delineate the molecular mechanisms of CDK8-operated metabolic control of vascular SMC dedifferentiation by 2 specific aims: Aim 1 will establish a mediator role of CDK8 in vascular SMC dedifferentiation into synthetic SMCs for intimal hyperplasia toward vascular occlusion; Aim 2 will determine the underlying molecular mechanisms with a focus on the molecular network by which CDK8 operates the mevalonate metabolism pathway for protein geranylgeranylation which is required for vascular SMC dedifferentiation into synthetic SMCs leading to intimal hyperplasia toward vascular occlusion. This proposal will provide the first assessment of CDK8-mediated occlusive vascular lesion formation and define a novel pathway of occlusive vascular remodeling that is mediated by previously unrecognized CDK8-operated metabolic reprogramming for vascular SMC dedifferentiation, thus shedding light on the study of vascular SMC plasticity as well as the development of innovative and effective therapeutic approaches for occlusive vascular disease.