This Article Full Text 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 Elhage, R. Articles by Arnal, J.-F. Search for Related Content PubMed PubMed Citation Articles by Elhage, R. Articles by Arnal, J.-F.

(Circulation. 1997;96:3048-3052.)
© 1997 American Heart Association, Inc.

Articles

Prevention of Fatty Streak Formation of 17ß-Estradiol Is Not Mediated by the Production of Nitric Oxide in Apolipoprotein E– Deficient Mice

R. Elhage, PhD; F. Bayard, MD, PhD; V. Richard, PhD; P. Holvoet, PhD; N. Duverger, PhD; C. Fiévet, PhD; ; J.-F. Arnal, MD, PhD

From INSERM U397 and Laboratoire de Physiologie, Institut L. Bugnard, Toulouse, France (R.E., F.B., J.-F.A.); Laboratoire de Pharmacologie, Faculté de Médecine, Rouen, France (V.R.); INSERM U325 et SERLIA, Institut Pasteur, Lille, France (C.F.); RPR-Gencell, Atherosclerosis Departement, Vitry sur Seine, France (N.D.); and Center for Molecular and Vascular Biology, Leuven, Belgium (P.H.).

Correspondence to J.F. Arnal, INSERM U397, Institut L. Bugnard, C.H.U. Rangueil, 1 ave Jean Poulhès, 31054 Toulouse Cedex, France. E-mail arnal{at}rangueil.inserm.fr

Background Estrogens have atheroprotective properties, the mechanisms of which remain obscure. Estrogens have recently been reported to increase endothelial NO synthase expression in castrated animals and to prevent the degradation of NO by decreasing superoxide anion production in cultured endothelial cells. In both cases, increased NO bioavailability would promote vasodilation, inhibit proliferation of the adjacent vascular smooth muscle, reduce platelet aggregation, and inhibit monocyte adhesion to the endothelium and the inflammatory reaction induced by cytokines, all key contributors in the development of atherosclerosis.

Methods and Results In the present work, the respective roles of 17ß-estradiol and NO in the development of the atherosclerotic process were investigated in castrated apolipoprotein E–deficient (apo E KO) mice, which spontaneously develop fatty streak lesions within 3 months. N-Nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, 50 mg · kg^-1 · d^-1, increased arterial blood pressure and decreased cerebellum cGMP content, demonstrating the blockade of NO production, but did not influence the atherogenic process in castrated apo E KO mice.

Conclusions 17ß-Estradiol decreased the size of the aortic lesions approximately threefold, and the magnitude of this vasculoprotective effect was not altered by L-NAME. Moreover, L-NAME increased circulating malonyldialdehyde (MDA)-modified LDL, which was not altered by 17ß-estradiol, leading to a complete dissociation between circulating MDA-modified LDL and parietal lesions.

Key Words: atherosclerosis • apolipoproteins • lipoproteins • endothelium

This article has been cited by other articles:

				A. Billon, S. Lehoux, L. Lam Shang Leen, H. Laurell, C. Filipe, V. Benouaich, L. Brouchet, C. Dessy, P. Gourdy, A.-P. Gadeau, et al. The Estrogen Effects on Endothelial Repair and Mitogen-Activated Protein Kinase Activation Are Abolished in Endothelial Nitric-Oxide (NO) Synthase Knockout Mice, but Not by NO Synthase Inhibition by N-Nitro-L-arginine Methyl Ester Am. J. Pathol., March 1, 2008; 172(3): 830 - 838. [Abstract] [Full Text] [PDF]

				R. M. Fitch, J. C. Rutledge, Y.-X. Wang, A. F. Powers, J.-L. Tseng, T. Clary, and G. M. Rubanyi Synergistic effect of angiotensin II and nitric oxide synthase inhibitor in increasing aortic stiffness in mice Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1190 - H1198. [Abstract] [Full Text] [PDF]

				P. Y. Liu, A. K. Death, and D. J. Handelsman Androgens and Cardiovascular Disease Endocr. Rev., June 1, 2003; 24(3): 313 - 340. [Abstract] [Full Text] [PDF]

				K. Yamahara, H. Itoh, T.-H. Chun, Y. Ogawa, J. Yamashita, N. Sawada, Y. Fukunaga, M. Sone, T. Yurugi-Kobayashi, K. Miyashita, et al. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration PNAS, March 18, 2003; 100(6): 3404 - 3409. [Abstract] [Full Text] [PDF]

				J. B. Hodgin and N. Maeda Minireview: Estrogen and Mouse Models of Atherosclerosis Endocrinology, December 1, 2002; 143(12): 4495 - 4501. [Abstract] [Full Text] [PDF]

				B. Darblade, C. Pendaries, A. Krust, S. Dupont, M.-J. Fouque, J. Rami, P. Chambon, F. Bayard, and J.-F. Arnal Estradiol Alters Nitric Oxide Production in the Mouse Aorta Through the {alpha}-, but not {beta}-, Estrogen Receptor Circ. Res., March 8, 2002; 90(4): 413 - 419. [Abstract] [Full Text] [PDF]

				R. K. Dubey and E. K. Jackson Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms Am J Physiol Renal Physiol, March 1, 2001; 280(3): F365 - F388. [Abstract] [Full Text] [PDF]

				S. Wassmann, A. T. Baumer, K. Strehlow, M. van Eickels, C. Grohe, K. Ahlbory, R. Rosen, M. Bohm, and G. Nickenig Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats Circulation, January 23, 2001; 103(3): 435 - 441. [Abstract] [Full Text] [PDF]

				M. Noris, M. Todeschini, S. Zappella, S. Bonazzola, C. Zoja, D. Corna, F. Gaspari, F. Marchetti, S. Aiello, and G. Remuzzi 17beta -Estradiol corrects hemostasis in uremic rats by limiting vascular expression of nitric oxide synthases Am J Physiol Renal Physiol, October 1, 2000; 279(4): F626 - F635. [Abstract] [Full Text] [PDF]

				T. Hayashi, M. Jayachandran, D. Sumi, N. K. Thakur, T. Esaki, E. Muto, H. Kano, Y. Asai, and A. Iguchi Physiological Concentration of 17{beta}-Estradiol Retards the Progression of Severe Atherosclerosis Induced by a High-Cholesterol Diet Plus Balloon Catheter Injury : Role of NO Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1613 - 1621. [Abstract] [Full Text] [PDF]

				K. Kauser, V. da Cunha, R. Fitch, C. Mallari, and G. M. Rubanyi Role of endogenous nitric oxide in progression of atherosclerosis in apolipoprotein E-deficient mice Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1679 - H1685. [Abstract] [Full Text] [PDF]

				L. Zhang, M. C. Fishman, and P. L. Huang Estrogen Mediates the Protective Effects of Pregnancy and Chorionic Gonadotropin in a Mouse Model of Vascular Injury Arterioscler Thromb Vasc Biol, September 1, 1999; 19(9): 2059 - 2065. [Abstract] [Full Text] [PDF]

				C. A. D. Nascimento, K. Kauser, and G. M. Rubanyi Effect of 17beta -estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1788 - H1794. [Abstract] [Full Text] [PDF]

				B. Darblade, C. Pendaries, A. Krust, S. Dupont, M.-J. Fouque, J. Rami, P. Chambon, F. Bayard, and J.-F. Arnal Estradiol Alters Nitric Oxide Production in the Mouse Aorta Through the {alpha}-, but not {beta}-, Estrogen Receptor Circ. Res., March 8, 2002; 90(4): 413 - 419. [Abstract] [Full Text] [PDF]