Oxidized LDL increases the sensitivity of the contractile apparatus in isolated resistance arteries for Ca2+ via a Rho- and Rho kinase-dependent mechanism

Background-Oxidized LDL reduces NO-mediated and endothelium-derived hyperpolarizing factor-mediated dilations. We studied, in hamster skeletal muscle resistance arteries (213+/-8 mum; n=51), whether an altered vascular smooth muscle (VSM) response, particularly sensitization of the VSM contractile apparatus to Ca2+, is involved in this oxLDL effect. Methods and Results-VSM or endothelial [Ca2+](i) and vascular diameter were measured in response to norepinephrine (0.3 mu mol/L), sodium nitroprusside (10 mu mol/L), C-type natriuretic peptide (1 to 100 nmol/L), papaverine (0.1 to 10 mu mol/L), or the endothelial agonist acetylcholine (ACh, 0.01 to 1 mu mol/L. OxLDL significantly increased resting VSM [Ca2+](i) (11 +/- 3%), decreased diameter (8 +/- 2%), and enhanced norepinephrine-induced constrictions. Dilations to sodium nitroprusside and C-type natriuretic peptide were significantly reduced roy 10 +/- 2% and 35 +/- 6%), whereas dose-response curves for papaverine and ACh were shifted to the right, despite unchanged increases in endothelial Ca2+ after ACh. OxLDL significantly shifted the Ca2+-diameter relation to the left, as assessed by stepwise increasing extracellular Ca2+ (0 to 3 mmol/L) in depolarized skeletal muscle resistance arteries. This sensitization to Ca2+ by oxLDL was abolished after inhibition of Rho (C3 transferase) or Rho kinase (Y27632). Conclusions-OxLDL reduces VSM responsiveness to vasodilators by increasing VSM Ca2+ but preferentially by sensitizing VSM to Ca2+ via a Rho- and Rho kinase-dependent pathway.