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

Abstract

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.

Functional properties of ion channels and transporters in tumour vascularization

“…HMEC, human microvascular EC; HPAEC, human pulmonary artery EC; HUVEC, human umbilical vein EC; EA.hy926, EC line derived from HUVEC fused with human lung adenocarcinoma cell line A549; PAEC, porcine aortic endothelial cells; BTEC, tumour-derived EC from breast carcinoma; H5VEC, heart endothelioma (H5V) EC; MAEC, mouse aortic EC; EPC, endothelial progenitor cells; RCC-EPC, EPC isolated from renal carcinoma patients; Numbers in parenthesis indicate the respective reference number. EPC [30] HMEC [31] BTEC [32] RCC-EPC [29] HUVEC [33 -35] HUVEC [36] HUVEC [37] HUVEC [38] HUVEC [36,39] MAEC from KO mice [40] HMEC [41,42] EPC [43] survival and proliferation RCC-EPC [29] EPC [30] HMEC [31] HUVEC [44] PAEC [45] H5V EC [46] HUVEC [40] HUVEC, HMEC [41,55] EPC [43] permeability HMEC,HUVEC [56 -58] HPAEC [59] Frog mesenteric microvessels [60] H5V EC [46] HUVEC [61] in vivo angiogenesis zebrafish [62] CAM [44] collateral growth [45] HERG-1-Retinoblastoma [63] EAG1-Xenograft in SCID mice and human osteosarcoma [27,28] CAM [54] xenograft in nude mice [38] Rabbit cornea [64] human mammary carcinoma, glioblastoma [65,66] AQP1 KO mice and C57BL/ 6 mice …”

“…In particular, a7 nAChR mediates the main effects of nicotine on EC, such as proliferation, survival, migration, tube formation and intracellular signalling. Interestingly, a9 and a7 nAChRs exert opposing effects on nicotine-induced cell proliferation and survival [41,42,69].…”

Regulation of Bone Marrow Stem Cells through Oscillatory Shear Stresses - A Heart Valve Tissue Engineering Perspective

“…have been systematically shown to be involved in angiogenesis, and in particular the α7 nACHR homomer [100] , [101], [102] , [114], [115]. Initial activation of an angiogenic pathway can either be endogenous via the agonist acetylcholine or by the external stimulant, Nicotine.…”

“…Initial activation of an angiogenic pathway can either be endogenous via the agonist acetylcholine or by the external stimulant, Nicotine. Extensive subsequent studies by the Cooke group at Stanford have shown that the fundamental mechanism by which Nicotine in low doses (10 -8 to 10 -6 M) promotes endothelial cell migration, proliferation and tube formation is the augmented permeability of Ca 2+ into the cell cytoplasm again via modulation of α7 nACHR( [101], [114], [115], [116] ). This in turn activates kinases responsible for heightened EC activity.…”

“…OSS has previously been hypothesized to be an important mechanical metric for heart valves [96] , [97] . For the biochemical factor we hypothesized that a small concentration of Nicotine (10 -6 M) which has previously served to promote vasculognesis may potentially promote a valvular endothelium for BMMSC-derived tissue engineered heart valves [98], [99], [100], [101], [102], [103] . Ironically, both OSS and Nicotin are known antagonists in cardiovascular disease; yet we postulated that these unusual suspects would have a beneficial effect in promoting mesenchymal to endothelial transformation, which in turn would support the formation of an engineered valve endothelium.…”