A Possible Role of Perivascular Adipocyte Stress in Cardiovascular Dysfunction Prior to the Onset of Diabetes

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality among diabetic patients. Although prolonged exposure to hyperglycemia is implicated in the pathogenesis of cardiovascular dysfunction, a significant proportion of patients show established diabetic microvascular complications at initial diagnosis of diabetes, before overt hyperglycemia. Moreover, recent studies from our laboratory have shown that cardiovascular dysfunction is evident in animal models of metabolic challenge before the onset of hyperglycemia and diabetes, thus placing the etiology of this early cardiovascular dysfunction in question. Given the role of adipose tissue inflammation in the pathophysiology of metabolic syndrome, we hypothesized that interactions between perivascular adipose tissue and vascular smooth muscle cells may play a role in early cardiovascular dysfunction. To test this hypothesis, 3T3‐L1 cells were differentiated to adipocyte‐like cells and treated with 1600 μM free fatty acids and 40 mIU/L insulin, mimicking the levels of these mediators in the plasma of rats challenged with 12 weeks of hyper‐caloric diet feeding. The conditioned medium from these cells was used to treat rat aortic vascular smooth muscle cells (VSMC). VSMC metabolic activity and expression of contractile phenotype markers were assessed. A decrease in metabolic activity in MTS assays was observed in cells treated with conditioned media from challenged 3T3 cells compared to those exposed to control media containing the same levels of fatty acids and/or insulin and to those exposed to conditioned media from control 3T3‐L1 cells. This was paralleled with a significant decrease in alpha‐smooth muscle actin in cells treated with conditioned media from stressed 3T3‐L1 cells. Significantly, media with high free fatty acids and/or insulin did not have a direct effect on VSMCs, supporting the idea that metabolic dysfunction‐evoked vascular impairment was induced by adipose tissue inflammation and suggesting the potential involvement of a soluble adipose tissue mediator triggered by the early insult on adipocytes. Furthermore, adipocyte‐differentiated human bone marrow mesenchymal stem cells challenged with the same concentrations of free fatty acids and insulin recruited a greater number of THP‐1 monocytes compared to cells exposed to control medium, suggesting an upregulation of monocyte attractant properties of stressed adipocytes consistent with an inflammatory phenotype. Our preliminary results indicate a possible mechanistic framework whereby metabolic challenge may mediate early VSMC dysfunction prior to overt hyperglycemia.Support or Funding InformationSupported 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.