This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bolz, S.-S. Articles by Pohl, U. Search for Related Content PubMed PubMed Citation Articles by Bolz, S.-S. Articles by Pohl, U. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL NITROUS OXIDE PAPAVERINE HYDROCHLORIDE Related Collections Pathophysiology Calcium cycling/excitation-contraction coupling Cell signalling/signal transduction Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Circulation. 2000;102:2402.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Oxidized LDL Increases the Sensitivity of the Contractile Apparatus in Isolated Resistance Arteries for Ca²⁺ via a Rho- and Rho Kinase–Dependent Mechanism

Steffen-Sebastian Bolz, MD; Jan Galle, MD, PhD; Roland Derwand; Cor de Wit, MD; Ulrich Pohl, MD, PhD

From the Physiologisches Institut, Ludwig Maximilians Universität, München, and the Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg (J.G.), Germany.

Correspondence to Steffen-Sebastian Bolz, Physiologisches Institut der Ludwig Maximilians Universität, Pettenkoferstraße 12, D-80336 München, Germany. E-mail bolz{at}lrz.uni-muenchen.de

Background—Oxidized LDL reduces NO-mediated and endothelium-derived hyperpolarizing factor–mediated dilations. We studied, in hamster skeletal muscle resistance arteries (213±8 µm; 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 µmol/L), sodium nitroprusside (10 µmol/L), C-type natriuretic peptide (1 to 100 nmol/L), papaverine (0.1 to 10 µmol/L), or the endothelial agonist acetylcholine (ACh, 0.01 to 1 µmol/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 (by 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.

Key Words: muscle, smooth • endothelium • endothelium-derived factors • atherosclerosis

This article has been cited by other articles:

				H.-W. Wang, P.-Y. Liu, N. Oyama, Y. Rikitake, S. Kitamoto, J. Gitlin, J. K. Liao, and W. A. Boisvert Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice FASEB J, October 1, 2008; 22(10): 3561 - 3570. [Abstract] [Full Text] [PDF]

				M. A. Allison, E. O. Lillie, D. DiTomasso, C. M. Wright, and M. H. Criqui Renal Artery Calcium Is Independently Associated With Hypertension J. Am. Coll. Cardiol., October 16, 2007; 50(16): 1578 - 1583. [Abstract] [Full Text] [PDF]

				T. A. Parker, G. Roe, T. R. Grover, and S. H. Abman Rho kinase activation maintains high pulmonary vascular resistance in the ovine fetal lung Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L976 - L982. [Abstract] [Full Text] [PDF]

				J. J. Maguire, K. E. Wiley, R. E. Kuc, V. E. A. Stoneman, M. R. Bennett, and A. P. Davenport Endothelin-Mediated Vasoconstriction in Early Atherosclerosis Is Markedly Increased in ApoE-/- Mouse but Prevented by Atorvastatin. Experimental Biology and Medicine, June 1, 2006; 231(6): 806 - 812. [Abstract] [Full Text] [PDF]

				K. Budzyn, M. Paull, P. D. Marley, and C. G. Sobey Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 791 - 796. [Abstract] [Full Text] [PDF]

				L. Y. W. Bourguignon, P. A. Singleton, and F. Diedrich Hyaluronan-CD44 Interaction with Rac1-dependent Protein Kinase N-{gamma} Promotes Phospholipase C{gamma}1 Activation, Ca2+ Signaling, and Cortactin-Cytoskeleton Function Leading to Keratinocyte Adhesion and Differentiation J. Biol. Chem., July 9, 2004; 279(28): 29654 - 29669. [Abstract] [Full Text] [PDF]

				A. P. SOMLYO and A. V. SOMLYO Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase Physiol Rev, October 1, 2003; 83(4): 1325 - 1358. [Abstract] [Full Text] [PDF]

				S.-S. Bolz, L. Vogel, D. Sollinger, R. Derwand, C. Boer, S. M. Pitson, S. Spiegel, and U. Pohl Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase Circulation, July 22, 2003; 108(3): 342 - 347. [Abstract] [Full Text] [PDF]

				S.-S. Bolz, L. Vogel, D. Sollinger, R. Derwand, C. de Wit, G. Loirand, and U. Pohl Nitric Oxide-Induced Decrease in Calcium Sensitivity of Resistance Arteries Is Attributable to Activation of the Myosin Light Chain Phosphatase and Antagonized by the RhoA/Rho Kinase Pathway Circulation, June 24, 2003; 107(24): 3081 - 3087. [Abstract] [Full Text] [PDF]

				J. Galle, A. Mameghani, S.-S. Bolz, S. Gambaryan, M. Gorg, T. Quaschning, U. Raff, H. Barth, S. Seibold, C. Wanner, et al. Oxidized LDL and its Compound Lysophosphatidylcholine Potentiate AngII-Induced Vasoconstriction by Stimulation of RhoA J. Am. Soc. Nephrol., June 1, 2003; 14(6): 1471 - 1479. [Abstract] [Full Text] [PDF]

				M. P. Massett, Z. Ungvari, A. Csiszar, G. Kaley, and A. Koller Different roles of PKC and MAP kinases in arteriolar constrictions to pressure and agonists Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2282 - H2287. [Abstract] [Full Text] [PDF]

				H.-M. Shin, H.-D. Je, C. Gallant, T. C. Tao, D. J. Hartshorne, M. Ito, and K. G. Morgan Differential Association and Localization of Myosin Phosphatase Subunits During Agonist-Induced Signal Transduction in Smooth Muscle Circ. Res., March 22, 2002; 90(5): 546 - 553. [Abstract] [Full Text] [PDF]

				M. A. Hill, H. Zou, S. J. Potocnik, G. A. Meininger, and M. J. Davis Signal Transduction in Smooth Muscle: Invited Review: Arteriolar smooth muscle mechanotransduction: Ca2+ signaling pathways underlying myogenic reactivity J Appl Physiol, August 1, 2001; 91(2): 973 - 983. [Abstract] [Full Text] [PDF]

				H.-M. Shin, H.-D. Je, C. Gallant, T. C. Tao, D. J. Hartshorne, M. Ito, and K. G. Morgan Differential Association and Localization of Myosin Phosphatase Subunits During Agonist-Induced Signal Transduction in Smooth Muscle Circ. Res., March 22, 2002; 90(5): 546 - 553. [Abstract] [Full Text] [PDF]