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 alpha(2), alpha(4), gamma, and delta in four different types of ECs. Using siRNA methodology, we found that the alpha(7) 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 alpha(9) and alpha(7) nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the alpha(7) 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.
Wu
Jenny C F
JC
Department of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
Chruscinski
Andrzej
A
De Jesus Perez
Vinicio A
VA
Singh
Harvir
H
Pitsiouni
Maria
M
Rabinovitch
Marlene
M
Utz
Paul J
PJ
Cooke
John P
JP
D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D018678:Cholinergic Agents / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016555:Matched-Pair Analysis; D009389:Neovascularization, Pathologic; D009538:Nicotine / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D040081:Protein Array Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor; D051176:beta Catenin / Q000378:metabolism
D018678:Cholinergic Agents; C579167:Chrna7 protein, human; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D051176:beta Catenin; D009569:Nitric Oxide; D009538:Nicotine; D015689:Oncogene Protein p21(ras)