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(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

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