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CLINICAL STUDY: WINE, NICOTINE, AND CARDIOVASCULAR DISEASE

Nicotine promotes arteriogenesis

Christopher Heeschen, MD^*, Michael Weis, MD^* and John P. Cooke, MD, PhD, FACC^*,*

^* Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany

Manuscript received November 21, 2001; revised manuscript received July 31, 2002, accepted August 20, 2002.

^* Reprint requests and correspondence: Dr. John P. Cooke, Stanford University School of Medicine, CV Med, 300 Pasteur Drive, Falk CVRC, Stanford, California 94305-5406, USA.
john.cooke{at}stanford.edu

OBJECTIVES: In the current study, we used a model of limb ischemia to determine whether nicotine could enhance arteriogenesis, to compare the magnitude of this effect to the angiogenic factor basic fibroblast growth factor (bFGF), and to investigate the mechanisms of the effect.

BACKGROUND: We have shown previously that nicotine stimulates angiogenesis via stimulation of endothelial nicotinic cholinergic receptors. Stimulation of endothelial nicotinic cholinergic receptors causes endothelial cell proliferation, migration, and formation of capillary networks in vitro and angiogenesis in vivo in conditions of ischemia and inflammation.

METHODS: New Zealand White rabbits (n = 85) underwent unilateral femoral artery occlusion and were randomized to nicotine (0.05 to 5.0 µg/kg/day), bFGF (10 µg/kg/day), or vehicle delivered intra-arterially via osmotic minipumps. At day 21, morphologic changes were assessed by immunohistochemistry and angiography. Blood flow in the ischemic limb was determined by intra-arterial Doppler flow measurements and microsphere distribution.

RESULTS: Nicotine enhanced capillary density in the ischemic hind-limb to a similar extent as bFGF. Nicotine also increased angiographic score, calf blood pressure ratio, intra-arterial Doppler flow, and microsphere distribution. In vitro, nicotine stimulated monocyte adhesion and transmigration. Nicotine increased by two- to three-fold the expression of monocyte adhesion molecules CD11b and CD11a; the expression of the endothelial adhesion molecule intercellular adhesion molecule-1; and the endothelial release of monocyte chemoattractant protein-1.

CONCLUSIONS: In the short term, nicotine promotes angiogenesis and arteriogenesis in the setting of ischemia. The effect of nicotine may be mediated in part by activation of endothelial-monocyte interactions involved in arteriogenesis.

Abbreviations and Acronyms   APV   average peak velocity   bFGF   basic fibroblast growth factor   CI   confidence interval   ECs   endothelial cells   HBSS   Hank’s balanced salt solution   HUVECs   human umbilical vein endothelial cells   ICAM-1   intercellular adhesion molecule-1   MCP-1   monocyte chemoattractant protein-1   nAChRs   nicotinic acetylcholine receptors   PBS   phosphate-buffered saline   TNF   tumor necrosis factor

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