Abstract 531: Role of Insulin Resistance in the Altered Vascular Relaxation Mechanisms and Hypertension in Caveolin-1 Deficient Mice

Abstract

Insulin resistance (IR) and endothelial dysfunction are often associated with hypertension; however, the specific causality and genetic underpinnings of these associations are unclear. Caveolin-1 (cav-1) is a transmembrane anchoring protein and potential modulator of vascular function and insulin sensitivity of the vascular and metabolic pathways. Our recent findings point to a role for cav-1 in IR, endothelial dysfunction and hypertension. In humans, cav-1 gene variants are associated with IR in hypertensive individuals. In mice, cav-1 deficiency leads to changes in endothelial function, IR and blood pressure (BP). To test whether the vascular changes associated with cav-1 deficiency are related to or are independent of IR, we assessed BP, blood glucose and vascular function in WT and cav-1 KO mice treated with placebo or metformin 400 mg/Kg/day for 21 days. BP was greater in cav-1 KO vs WT (140.1±2.1 vs 116.5±1.3 mmHg), and metformin treatment did not change BP in cav-1 KO (140.7±1.4) or WT (112.5±1.6 mmHg). Fasting blood glucose was greater in cav-1 KO vs WT (112±3.9 vs. 83.1±4.4 mg/dl), supporting a link between cav-1 deficiency and IR. Metformin did not change blood glucose levels in cav-1 KO (110.4±4.1) or WT (86.7±8.2 mg/dl). Acetylcholine (ACh)-induced maximal aortic relaxation was greater in cav-1 KO vs WT (85.3±5.7 vs. 17.5±4.4%), and was abolished by endothelium removal or the NOS inhibitor L-NAME, supporting changes in endothelial NO production/signaling. Metformin reduced ACh relaxation in cav-1 KO to 60.7±6.6%, but had no effect in WT. The exogenous NO donor sodium nitroprusside (SNP) produced similar maximal relaxation in cav-1 KO and WT (98.4±1.6 and 98.2±1.1%), but was more potent in cav-1 KO vs WT (pEC50, 8.6 vs 8.1). Metformin reduced SNP relaxation in cav-1 KO (84.9±6.4%) but not in WT, and reversed the enhanced sensitivity to SNP in cav-1 KO mice. The metformin-induced decrease in vascular relaxation and sensitivity to NO in cav-1 KO mice suggests a role for vascular IR in the changes in endothelial function. The lack of effect of metformin on fasting blood glucose in cav-1 KO mice suggests recalcitrant IR of the metabolic pathways. Together, these data support partial independence of vascular function from systemic IR in cav-1 deficiency states.