Phenotypic alteration of vascular smooth muscle cells as a sequence of mild hyper‐caloric intake in the absence of hyperglycemia: Potential modulation by antidiabetic drugs

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Diabetic patients remain at a high risk of atherosclerotic cardiovascular disease in addition to hypertension and microvascular complications. A significant proportion of diabetic patients present with vascular abnormalities upon initial diagnosis implicating an early vascular insult in the course of development of diabetes. A contractile‐to‐synthetic vascular smooth muscle cell (VSMC) phenotypic switch is associated with different diseases including atherosclerosis, diabetes, hypertension, and cancer. In the present study, we examined whether early metabolic derangement in the course of diabetes development was associated with VSMC phenotypic alteration before hyperglycemia develops. For this purpose, we used a high‐calorie diet (HC) fed rat model with delayed development of hyperglycemia. Up to 12 weeks of feeding, neither increased serum glucose nor elevated mean arterial pressure was detected. Control and HC rats were sacrificed at 4, 8, and 12 weeks, and their aortae were dissected for isolation of primary VSMCs. VSMC morphology changed whereby the typical hill‐and‐valley culture pattern was gradually substituted by densely packed areas of rhomboid cells in explants for aortic tissues from HC rats. This changed appeared to be dependent on the duration of feeding. VSMC proliferation and migration increased in cultures derived from HC‐fed rats compared to controls at the same age and passage number. Moreover, VSMC contractile phenotype markers smooth muscle alpha actin and calponin gradually decreased in cells cultured from HC‐fed rats in a manner proportional to the feeding duration. In vitro, exposure to pioglitazone, but not metformin was associated with a reduction in VSMC proliferation in cells derived from HC‐fed rats. On the contrary, similar exposure to increased oleiate and palmitate concentrations in the culture medium resulted in an increased proliferation of VSMCs from control rats. Our results indicate that VSMC phenotype and function is potentially affected by the early metabolic derangement associated with the development of diabetes regardless of the blood glucose concentration. Studies to investigate the effect of chronic exposure of HC‐fed rats to metformin and pioglitazone on VSMC phenotype are underway.Support or Funding InformationSupported by AUB MPP fund #320148This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.