Cholinergic modulation of angiogenesis: Role of the 7 nicotinic acetylcholine receptor

Pathological angiogenesis contributes to tobacco-related diseases such as malignancy, atherosclerosis and age-related macular degeneration. Nicotine acts on endothelial nicotinic acetylcholine receptors (nAChRs) to activate endothelial cells and to augment pathological angiogenesis. In the current study, we studied nAChR subunits involved in these actions. We detected mRNA for all mammalian nAChR subunits except α₂, α₄, γ, and δ in four different types of ECs. Using siRNA methodology, we found that the α₇ nAChR plays a dominant role in nicotine-induced cell signaling (assessed by intracellular calcium and NO imaging, and studies of protein expression and phosphorylation), as well as nicotine-activated EC functions (proliferation, survival, migration, and tube formation). The α₉ and α₇ nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the α₇ nAChR in mediating the effects of nicotine on the endothelium. Other subunits play a modulatory role. These findings may have therapeutic implications for diseases characterized by pathological angiogenesis.