This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 De Meyer, G. R. Y. Articles by Bult, H. Search for Related Content PubMed PubMed Citation Articles by De Meyer, G. R. Y. Articles by Bult, H.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1896.)
© 2000 American Heart Association, Inc.

Vascular Biology

Periadventitial Inducible Nitric Oxide Synthase Expression and Intimal Thickening

Guido R. Y. De Meyer; Mark M. Kockx; Kristel M. Cromheeke; Cheikh I. Seye; Arnold G. Herman; Hidde Bult

From the Divisions of Pharmacology (G.R.Y.D.M., M.M.K., C.I.S., A.G.H., H.B.) and Cardiology (K.M.C.), University of Antwerp (UIA); and the Department of Pathology (M.M.K.), General Hospital Middelheim, Antwerp, Belgium.

Correspondence to Guido R.Y. De Meyer, Division of Pharmacology, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Wilrijk, Belgium. E-mail gdemeyer{at}uia.ua.ac.be

Abstract—Positioning a silicone collar around the rabbit carotid artery induces a smooth muscle cell–rich intimal thickening. We investigated the localization of inducible nitric oxide synthase (iNOS) during thickening of the intima, the effect of iNOS inhibition on intimal thickness, and the effect of oxidized LDL (ox-LDL) on iNOS expression in the vessel wall. Collars were positioned for 18 hours or for 3, 7, or 14 days. Arterial cross sections were immunostained for iNOS, including naïve, sham-operated, and carotid arteries in which ox-LDL had been infused locally for 14 days. Furthermore, collars were connected to osmotic minipumps for local delivery (5 µL · h^-1, 14 days, n=12) of saline or the iNOS inhibitor L-N⁶-(1-iminoethyl)-lysine-HCl (L-NIL, 10 mmol/L). In the adventitia and the periadventitial granulation tissue of collared arteries, iNOS-positive macrophages and T lymphocytes were present from 18 hours onward. The media and intima were negative for iNOS. Reverse transcription–polymerase chain reaction revealed iNOS mRNA in collared but not in sham-operated arteries. Local inhibition of iNOS doubled the intimal thickness and decreased nitrotyrosine staining. Ox-LDL–treated arteries, which had a thicker intima, showed a pronounced influx of macrophages and T lymphocytes in all layers of the vessel wall, accompanied by iNOS expression in a subpopulation of these cells. Our study indicates that iNOS was not induced in intimal thickenings predominantly consisting of smooth muscle cells. However, iNOS was expressed in (peri)adventitial tissue and counteracted the progression of intimal thickening. Ox-LDL treatment was accompanied by an abundant influx of iNOS-positive macrophages and T lymphocytes in the vessel, but this could not prevent the progression of intimal thickening.

Key Words: intima • oxidized LDL • nitric oxide • adventitia • local delivery

This article has been cited by other articles:

				V. Croons, W. Martinet, A. G. Herman, J.-P. Timmermans, and G. R. Y. De Meyer The Protein Synthesis Inhibitor Anisomycin Induces Macrophage Apoptosis in Rabbit Atherosclerotic Plaques through p38 Mitogen-Activated Protein Kinase J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 856 - 864. [Abstract] [Full Text] [PDF]

				V. Croons, W. Martinet, A. G. Herman, and G. R. Y. De Meyer Differential Effect of the Protein Synthesis Inhibitors Puromycin and Cycloheximide on Vascular Smooth Muscle Cell Viability J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 824 - 832. [Abstract] [Full Text] [PDF]

				V. Croons, W. Martinet, A. G. Herman, J.-P. Timmermans, and G. R. Y. De Meyer Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 986 - 993. [Abstract] [Full Text] [PDF]

				S. Verheye, W. Martinet, M. M. Kockx, M. W.M. Knaapen, K. Salu, J.-P. Timmermans, J. T. Ellis, D. L. Kilpatrick, and G. R.Y. De Meyer Selective Clearance of Macrophages in Atherosclerotic Plaques by Autophagy J. Am. Coll. Cardiol., February 13, 2007; 49(6): 706 - 715. [Abstract] [Full Text] [PDF]

				P. J. Pagano and M. J. Haurani Vascular Cell Locomotion: Osteopontin, NADPH Oxidase, and Matrix Metalloproteinase-9 Circ. Res., June 23, 2006; 98(12): 1453 - 1455. [Full Text] [PDF]

				R. Khurana, S. Shafi, J. Martin, and I. Zachary Vascular Endothelial Growth Factor Gene Transfer Inhibits Neointimal Macrophage Accumulation in Hypercholesterolemic Rabbits Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1074 - 1080. [Abstract] [Full Text] [PDF]

				C. I. Seye, Q. Kong, L. Erb, R. C. Garrad, B. Krugh, M. Wang, J. T. Turner, M. Sturek, F. A. Gonzalez, and G. A. Weisman Functional P2Y2 Nucleotide Receptors Mediate Uridine 5'-Triphosphate-Induced Intimal Hyperplasia in Collared Rabbit Carotid Arteries Circulation, November 19, 2002; 106(21): 2720 - 2726. [Abstract] [Full Text] [PDF]

				J. M. STULAK, A. LERMAN, M. R. PORCEL, J. A. CACCITOLO, J. C. ROMERO, H. V. SCHAFF, C. NAPOLI, and L. O. LERMAN Renal Vascular Function in Hypercholesterolemia Is Preserved by Chronic Antioxidant Supplementation J. Am. Soc. Nephrol., September 1, 2001; 12(9): 1882 - 1891. [Abstract] [Full Text] [PDF]

				H. E. von der Leyen and V. J. Dzau Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation Circulation, June 5, 2001; 103(22): 2760 - 2765. [Full Text] [PDF]