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Role of Non-neuronal Nicotinic Acetylcholine Receptors in Angiogenesis Modulation

  • Shaker A. Mousa
  • Hugo R. Arias
  • Paul J. Davis
Chapter

Abstract

Angiogenesis is a critical physiological process for cell survival and development. Endothelial cells, necessary for the course of angiogenesis, express several non-neuronal nicotinic acetylcholine receptors (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 αvβ3 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 revascularization such as diabetic ischemia and foot ulcer, as well as to accelerate wound-healing. In this chapter we discuss the pharmacological evidence supporting the importance of non-neuronal AChRs in angiogenesis. We also explore potential intracellular mechanisms by which α7 AChR activation mediates this vital cellular process.

Keywords

Vascular Endothelial Growth Factor Vascular Endothelial Growth Factor Expression Choroidal Neovascularization Vascular Endothelial Growth Factor Inhibitor AChR Subunit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

α-BTx

α-bungarotoxin

ACh

acetylcholine

AChR

nicotinic acetylcholine receptor

Akt

protein kinase B

BDNF

brain-derived neurotrophic factor

bFGF (FGF2)

basic fibroblast growth factor

CAM

chorioallantoic membrane

COX-2

cyclooxygenase-2

DHβE

dihydro-β-erythroidine

DMPP

dimethylphenylpiperazinium

EC

endothelial cell

EGFR

epidermal growth factor receptor

ERK

extracellular signal-regulated kinase

FGF

fibroblast growth factor

FLT1

FMS-related tyrosine kinase-1

HIF-1

hypoxia-inducible factor-1

IKK

IκBα kinase

IL

interleukin

MAPK

mitogen-activated protein kinase

MEKK-1

MAPK/ERK kinase kinase-1

MMP

matrix metalloproteinase

NF-κB

nuclear factor-κB

NO

nitric oxide

NSCLC

non-small cell lung carcinoma

PDGF

platelet-derived growth factor

PDGFR

platelet-derived growth factor receptor

PI3K

phosphatidylinositol 3′-kinase

Rb

retinoblastoma protein

Src

Src kinase

TGF-α

transforming growth factor-α

TGF-β

transforming growth factor-β

TNF-α

tumor necrosis factor-α

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

XIAP

X-linked inhibitor of apoptosis

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Shaker A. Mousa
    • 1
  • Hugo R. Arias
    • 2
  • Paul J. Davis
    • 3
    • 4
  1. 1.The Pharmaceutical Research Institute at Albany College of Pharmacy and Health SciencesRensselaerUSA
  2. 2.Department of Medical Education, College of MedicineCalifornia North State UniversityElk GroveUSA
  3. 3.The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences AlbanyRensselaerUSA
  4. 4.Department of MedicineAlbany Medical CenterAlbanyUSA

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