We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.

Background-Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. Methods and Results-Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 mol/L) but significantly inhibited at high statin concentrations (0.05 to 1 mol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg · kg Ϫ1 · d Ϫ1 ) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg · kg Ϫ1 · d

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Abstract-Cardiac allograft vasculopathy (CAV) continues to limit the long-term success of cardiac transplantation.Recent insights have underscored the fact that innate and adaptive immune responses are involved in the pathogenesis of CAV. Vascular lesions are the result of cumulative endothelial injuries induced both by alloimmune responses and by nonspecific insults (including ischemia-reperfusion injury, viral infections, and metabolic disorders) in the context of impaired repair mechanisms. Intravascular ultrasound is the most sensitive method for detection of CAV, and progressive intimal thickening in the first posttransplant year identifies patients at high risk for future cardiovascular events. Encouraging results with regard to the detection of CAV by noninvasive methods should be an incentive to apply routine noninvasive imaging during mid-to long-term follow-up. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), have beneficial effects on CAV progression, although there is still a need to confirm the impact of vasodilators in improving outcome after heart transplantation. Coronary revascularization for CAV is only palliative, with no long-term survival benefit. Three main strategies for CAV prevention are currently under investigation: inhibition of growth factors and cytokines, cell therapy, and tolerance induction. However, because individual responses to an allograft change over time, assays to monitor the recipient's immune response and individualized methods for therapeutic immune modulation are clearly needed. (Circulation. 2008;117:2131-2141.)

Introduction Angiogenesis is a complex, combinatorial process that is regulated by a balance between pro-and antiangiogenic molecules (1). Angiogenic stimuli (e.g., hypoxia or inflammatory cytokines) induce the expression and release of angiogenic growth factors such as VEGF and FGF. These growth factors stimulate endothelial cells (ECs) in the existing vasculature to proliferate and to migrate through the tissue to form new endothelialized channels (1, 2). We have recently demonstrated that nicotine is a potent stimulus of angiogenesis (3). This unexpected effect of nicotine appears to be mediated by nicotinic acetylcholine receptors (nAChRs) (3). These nAChRs are ionotropic receptors, in this case agonist-regulated Ca 2+ channels. Neuronal and some non-neuronal cells (e.g., bronchial epithelial cells, ECs, smooth muscle cells, and skin keratinocytes) express nAChRs (4-6). Previously, we demonstrated that nicotine stimulates angiogenesis in the settings of inflammation, ischemia, tumor, or atherosclerosis. Nicotine promoted the growth of atherosclerotic plaques and tumors at least in part by stimulating pathological angiogenesis. However, acetylcholine is the endogenous agonist of nAChRs and is synthesized and stored in ECs and blood cells, suggesting that acetylcholine may act as an autocrine factor in the cardiovascular system (7, 8). It is likely that endogenous acetylcholine released from ECs activates endothelial nAChRs. We embarked upon the current study to determine whether activation of nAChRs is involved in endogenous angiogenic response. Methods Expression of nAChR. Human umbilical vein ECs (HUVECs; up to second passage) and human microvascular ECs (HMVECs; up to fourth passage; BioWhittaker Inc., Walkersville, Maryland, USA) were grown in EGM-2 supplemented with 10% FBS (BioWhittaker Inc.). The surface expression of the nAChRs was studied in subconfluent HUVECs (EBM supplemented with 0.5% FBS; BioWhittaker Inc.) after 12-hour nicotine stimulation (0.1 nM-1.0 µM; Sigma-Aldrich, St. Louis, Missouri, USA) or after exposure to hypoxia (3% oxygen).