title: Dissociation of hyperglycemia from altered vascular contraction and relaxation mechanisms in caveolin-1 null mice.
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.
authors.affiliation: Cardiovascular Endocrine Section, Endocrinology, Diabetes and Hypertension Division (L.H.P., T.M.Y., A.E.G., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., O.M.R., R.A.K.), Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Luminita H
authors.initials: LH
authors.lastname: Pojoga
authors.forename: Tham M
authors.initials: TM
authors.lastname: Yao
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Opsasnick
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Garza
authors.forename: Ossama M
authors.initials: OM
authors.lastname: Reslan
authors.forename: Gail K
authors.initials: GK
authors.lastname: Adler
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Williams
authors.forename: Raouf A
authors.initials: RA
authors.lastname: Khalil
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D055372:AMP-Activated Protein Kinases; D006162:Guanylate Cyclase