This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 23/9/1528    most recent 01.ATV.0000090129.75275.C2v1 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 Zeidan, A. Articles by Swärd, K. Search for Related Content PubMed PubMed Citation Articles by Zeidan, A. Articles by Swärd, K. Related Collections Hypertrophy Remodeling Restenosis Receptor pharmacology Cell signalling/signal transduction

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1528.)
© 2003 American Heart Association, Inc.

Vascular Biology

Cholesterol Dependence of Vascular ERK1/2 Activation and Growth in Response to Stretch

Role of Endothelin-1

Asad Zeidan; Jonas Broman; Per Hellstrand; Karl Swärd

From the Division of Molecular and Cellular Physiology, Department of Physiological Sciences, Lund University, Biomedical Centre, Lund, Sweden.

Correspondence to Karl Swärd, PhD, Department of Physiological Sciences, Lund University, BMC F12, SE-221 84 Lund, Sweden. E-mail karl.sward{at}mphy.lu.se

Objective— Stretch-induced growth of the vascular wall plays a role in hypertension and neointima formation. Its signal pathways involve integrins, cytoskeleton, membrane receptors, and ion channels, some of which are organized in cholesterol-rich, membrane domains such as lipid rafts or caveolae. This study tested the role of rafts/caveolae in stretch-induced vascular growth by manipulation of membrane cholesterol contents.

Methods and Results— Growth and protein synthesis were induced by mechanical stretch of rat portal veins in vitro. Sucrose gradient centrifugation showed stretch-induced tyrosine phosphorylation primarily in fractions containing caveolin-1. Disruption of membrane caveolae with use of methyl-ß-cyclodextrin (mßcd) reduced weight gain, protein synthesis, and DNA synthesis to levels in unstretched, control veins. These effects were partially reversed by restoration of cellular cholesterol contents. Inhibited growth was associated with abolished activation of extracellular signal–regulated kinase (ERK) 1/2 in response to stretch and endothelin-1 (ET-1) but not to angiotensin II. Inhibition of ET-1 type A (ET_A) receptors by RF139317 or endothelin-converting enzyme by phosphoramidone abolished stretch-induced ERK1/2 activation, which was, however, unaffected by removal of the endothelium.

Conclusions— Stretch-induced growth signaling in vascular smooth muscle depends on cholesterol-rich, membrane microdomains by a mechanism involving ET_A receptors that respond to endogenous ET-1 production.

Key Words: hypertrophy • portal vein • caveolae • ERK1/2 • cyclodextrin

This article has been cited by other articles:

				S. Albinsson, I. Nordstrom, K. Sward, and P. Hellstrand Differential dependence of stretch and shear stress signaling on caveolin-1 in the vascular wall Am J Physiol Cell Physiol, January 1, 2008; 294(1): C271 - C279. [Abstract] [Full Text] [PDF]

				A. Zeidan, B. Paylor, K. J. Steinhoff, S. Javadov, V. Rajapurohitam, S. Chakrabarti, and M. Karmazyn Actin Cytoskeleton Dynamics Promotes Leptin-Induced Vascular Smooth Muscle Hypertrophy via RhoA/ROCK- and Phosphatidylinositol 3-Kinase/Protein Kinase B-Dependent Pathways J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1110 - 1116. [Abstract] [Full Text] [PDF]

				M. N. Richard, J. F. Deniset, A. L. Kneesh, D. Blackwood, and G. N. Pierce Mechanical Stretching Stimulates Smooth Muscle Cell Growth, Nuclear Protein Import, and Nuclear Pore Expression through Mitogen-activated Protein Kinase Activation J. Biol. Chem., August 10, 2007; 282(32): 23081 - 23088. [Abstract] [Full Text] [PDF]

				S. Albinsson and P. Hellstrand Integration of signal pathways for stretch-dependent growth and differentiation in vascular smooth muscle Am J Physiol Cell Physiol, August 1, 2007; 293(2): C772 - C782. [Abstract] [Full Text] [PDF]

				M. Tosun, Y. Erac, C. Selli, and N. Karakaya Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase inhibition prevents endothelin A receptor antagonism in rat aorta Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1961 - H1966. [Abstract] [Full Text] [PDF]

				F. Peng, D. Wu, A. J. Ingram, B. Zhang, B. Gao, and J. C. Krepinsky RhoA Activation in Mesangial Cells by Mechanical Strain Depends on Caveolae and Caveolin-1 Interaction J. Am. Soc. Nephrol., January 1, 2007; 18(1): 189 - 198. [Abstract] [Full Text] [PDF]

				C. Dubroca, X. Loyer, K. Retailleau, G. Loirand, P. Pacaud, O. Feron, J.-L. Balligand, B. I. Levy, C. Heymes, and D. Henrion RhoA activation and interaction with Caveolin-1 are critical for pressure-induced myogenic tone in rat mesenteric resistance arteries Cardiovasc Res, January 1, 2007; 73(1): 190 - 197. [Abstract] [Full Text] [PDF]

				M. M. Vihanto, C. Vindis, V. Djonov, D. P. Cerretti, and U. Huynh-Do Caveolin-1 is required for signaling and membrane targeting of EphB1 receptor tyrosine kinase J. Cell Sci., June 1, 2006; 119(11): 2299 - 2309. [Abstract] [Full Text] [PDF]

				G. S. Hassan, T. M. Williams, P. G. Frank, and M. P. Lisanti Caveolin-1-deficient aortic smooth muscle cells show cell autonomous abnormalities in proliferation, migration, and endothelin-based signal transduction Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2393 - H2401. [Abstract] [Full Text] [PDF]

				A. Zeidan, D. M. Purdham, V. Rajapurohitam, S. Javadov, S. Chakrabarti, and M. Karmazyn Leptin Induces Vascular Smooth Muscle Cell Hypertrophy through Angiotensin II- and Endothelin-1-Dependent Mechanisms and Mediates Stretch-Induced Hypertrophy J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1075 - 1084. [Abstract] [Full Text] [PDF]

				C. G. Egan, C. L. Wainwright, R. M. Wadsworth, and G. F. Nixon PDGF-induced signaling in proliferating and differentiated vascular smooth muscle: Effects of altered intracellular Ca2+ regulation Cardiovasc Res, August 1, 2005; 67(2): 308 - 316. [Abstract] [Full Text] [PDF]

				A. Bergdahl, M. F. Gomez, A.-K. Wihlborg, D. Erlinge, A. Eyjolfson, S.-Z. Xu, D. J. Beech, K. Dreja, and P. Hellstrand Plasticity of TRPC expression in arterial smooth muscle: correlation with store-operated Ca2+ entry Am J Physiol Cell Physiol, April 1, 2005; 288(4): C872 - C880. [Abstract] [Full Text] [PDF]

				L. Liu, J. Abramowitz, A. Askari, and J. C. Allen Role of caveolae in ouabain-induced proliferation of cultured vascular smooth muscle cells of the synthetic phenotype Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2173 - H2182. [Abstract] [Full Text] [PDF]

				S. Albinsson, I. Nordstrom, and P. Hellstrand Stretch of the Vascular Wall Induces Smooth Muscle Differentiation by Promoting Actin Polymerization J. Biol. Chem., August 13, 2004; 279(33): 34849 - 34855. [Abstract] [Full Text] [PDF]

				J. Thyberg Caveolin-1 and Caveolae Act as Regulators of Mitogenic Signaling in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1481 - 1483. [Full Text] [PDF]