Abstract

Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav-1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1^−/− mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1^−/− mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1^−/− > WT and did not change with metformin. Phenylephrine (Phe)- and KCl-induced aortic contraction was in cav-1^−/− < WT; endothelium removal, the nitric-oxide synthase (NOS) blocker l-NAME (N^ω-nitro-l-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1^−/− > WT, abolished by endothelium removal, l-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1^−/− than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1^−/− > WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1^−/−. Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1^−/− mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states.