Mild Hypercaloric Intake is Associated with an Impaired Vascular Smooth Muscle Phenotype in Absence of Hyperglycemia: Potential Modulation by Anti‐diabetic Drugs

Cardiovascular disease is the leading cause of mortality and morbidity in diabetes. Diabetes‐induced vascular complications are associated with the contractile‐to‐synthetic phenotypic switch of the vascular smooth muscle cells (VSMCs). Emerging experimental and clinical data have shown that functionally impaired VSMCs contribute to the high incidence rates of macrovascular complications in diabetes. Moreover, a significant proportion of diabetic patients show signs of vascular impairment at initial presentation before prolonged exposure to hyperglycemia. The underlying mechanisms leading to VSMC deterioration, particularly in early stages of metabolic dysfunction, remain largely unknown. In this study, we have investigated VSMC phenotypic alterations in a model of early metabolic derangements. Rats fed a mild hypercaloric (MHC) diet were used at time points prior to the development of hyperglycemia. Aortic VSMCs were isolated from control rats, from MHC fed rats sacrificed after 4, 8, or 12 weeks of exposure. At twelve weeks, MHC‐fed rats did not show increased fasting or random blood glucose, impaired glucose tolerance, increased weight, or hypertension. The effect of a two‐week treatment with metformin and pioglitazone prior to sacrifice at the 12‐week time point was examined. A gradual reduction in VSMC activity in MTS assays was observed as a function of MHC‐feeding duration, with the sharpest decrease observed at 12 weeks. Cell cycle assays revealed no changes in cell proliferation indicating that the changes in MTS assays were rather a reduction in metabolic activity. Moreover, expression of VSMC contractile phenotype markers, a‐smooth muscle actin and calponin, decreased progressively with MHC feeding. Interestingly, in vivo treatment with non‐hypoglycemic doses of either metformin and pioglitazone, known to have positive vascular pleiotropic effects, restored VSMCs metabolic activity and contractile marker expression to control levels. Significantly, no changes were detected VSMC metabolic activity and contractile marker expression following in vitro exposure to either a range of concentrations of free fatty acids, to simulate the MHC diet effect, or to metformin or pioglitazone. The contrast between in vitro and in vivo results suggests a direct effect of lipids on VSMC phenotype and function is unlikely; however, the changes observed might be a result of a more complex interaction with more than one tissue type. We hypothesize that the observed effect of MHC diet is mediated by the induction of perivascular adipose inflammation. Studies are underway to verify this claim. Support or Funding Information Supported by AUB MPP fund #320148 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .