Nicotine promotes arteriogenesis.
OBJECTIVE
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 microg/kg/day), bFGF (10 microg/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.
Heeschen
Christopher
C
Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5406, USA.
Weis
Michael
M
Cooke
John P
JP
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000792:Angiography; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology* / Q000627:therapeutic use*; D005731:Ganglionic Stimulants / Q000494:pharmacology* / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D007866:Leg / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use*; D011817:Rabbits; D014471:Umbilical Veins / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology
D043925:Angiogenesis Inducing Agents; D005731:Ganglionic Stimulants; D016222:Fibroblast Growth Factor 2; D009538:Nicotine