Affiliations: The Pharmaceutical Research Institute, Albany College
of Pharmacy and Health Sciences, Albany, NY, USA | King Saud University, Riyadh, Saudi Arabia | Vascular Vision Pharmaceuticals Co, Rensselaer, NY,
USA | Department of Pharmaceutical Sciences, College of
Pharmacy, Midwestern University, Glendale, AZ, USA
Note: [] Correspondence: Shaker A. Mousa, Ph.D., MBA, FACC, FACB, Albany
College of Pharmacy and Health Sciences, 1 Discovery Drive (Room- 238),
Rensselaer, NY 12144, USA. Tel.: +1 518 694 7397; Fax: +1 518 694 7392; E-mail:
[email protected]
Abstract: Nicotine, one of the thousands of chemicals in cigarette smoke has a
highly debated effect on cell proliferation and tissue healing. Recent studies
documented its pro-angiogenesis effects by stimulating endothelial cell
α7 non-neronal nicotinic acetylcholine receptors (α7 AChR).
Angiogenesis is a critical physiological process for cell survival and
development. Endothelial cells, necessary for the course of angiogenesis,
express several non-neuronal AChRs. The most important functional non-neuronal
AChRs are homomeric α7 AChRs and several heteromeric AChRs formed by a
combination of α3, α5, β2, and β4 subunits, including
α3β4-containing AChRs. In endothelial cells, α7 AChR
stimulation indirectly triggers the activation of the integrin
α_{ν}β _{3} receptor and an
intracellular MAP kinase (ERK) pathway that mediates angiogenesis.
Non-selective cholinergic agonists such as nicotine have been shown to induce
angiogenesis, enhancing tumor progression. Moreover, α7 AChR selective
antagonists such as α-bungarotoxin and methyllycaconitine as well as the
nonspecific antagonist mecamylamine have been shown to inhibit endothelial cell
proliferation and ultimately blood vessel formation. Exploitation of such
pharmacologic properties can lead to the discovery of new specific cholinergic
antagonists as anti-cancer therapies. Conversely, the pro-angiogenic effect
elicited by specific agonists can be used to treat diseases that respond to
re-vascularization such as diabetic ischemia and atherosclerosis, as well as to
accelerate wound healing. In this review we discuss the pharmacological
evidence supporting the importance of non-neuronal AChRs in angiogenesis and
potential intracellular mechanisms by which α7 AChR activation mediates
these cellular processes.
