Nicotine and Cotinine Up-Regulate Vascular Endothelial Growth Factor Expression in Endothelial Cells

Conklin, Brian S.; Zhao, Weidong; Zhong, Diansheng; Chen, Changyi

doi:10.1016/s0002-9440(10)64859-6

Cited by 145 publications

(101 citation statements)

References 35 publications

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“…23,24 Most recently, it was shown that nicotine and its major metabolite cotinine up-regulate the expression of vascular endothelial growth factor (VEGF) in endothelial cells. 25 Changes in the expression of VEGF elicited by nicotine may help to explain the effects of this agent on atherosclerotic plaque neovascularization and tumor angiogenesis previously reported by our group. In this study the nAChR agonist, nicotine, significantly accelerated wound healing in diabetic mice.…”

Section: Discussionmentioning

confidence: 66%

Nicotine Accelerates Angiogenesis and Wound Healing in Genetically Diabetic Mice

Jacobi

Jang

Sundram

et al. 2002

The American Journal of Pathology

153

117

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Recently, we have discovered an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic acetylcholine receptors (nAChRs). Since angiogenesis plays a major role in wound repair, we hypothesized that activation of nAChRs with nicotine would accelerate wound healing in a murine excisional wound model. In genetically diabetic and control mice full-thickness skin wounds (0.8 cm) were created on the dorsum and topically treated over 7 days with either vehicle (phosphate-buffered saline, PBS) or nicotine (10 ؊8 mol/L, 10 ؊9 mol/L; each, n ‫؍‬ 5). Wound size was measured over 14 days followed by resection, histological analysis, and quantitation of vascularity. In diabetic animals an agonist (epibatidine, 10 ؊10 mol/L) or antagonist (hexamethonium, 10 ؊4 mol/L) of nAChRs as well as the positive control basic fibroblast growth factor (bFGF, 25 g/kg) were also tested. To further study the role of endothelial nAChRs in angiogenesis, we used an ex vivo vascular explant model. In diabetic mice wound healing was markedly impaired. Nicotine significantly accelerated wound healing as assessed by closure rate and histological score. The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium. Histomorphometry revealed increased neovascularization in animals treated with nicotine. Furthermore, capillary-like sprouting from vascular explants was significantly enhanced by nicotine. In conclusion, agonist-induced stimulation of nAChRs accelerates wound healing in diabetic mice by promoting angiogenesis. We have discovered a cholinergic pathway for angiogenesis that is involved in wound healing, and which is a potential target for therapeutic angiogenesis.

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Section: Discussionmentioning

confidence: 66%

Nicotine Accelerates Angiogenesis and Wound Healing in Genetically Diabetic Mice

Jacobi

Jang

Sundram

et al. 2002

The American Journal of Pathology

153

117

View full text Add to dashboard Cite

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“…It has been found that in non-neuronal tissues nicotine induces the secretion of growth factors like bFGF, TGF-α, VEGF, and PDGF (18), upregulation of the calpain family of proteins (19) as well as COX-2 and VEGFR-2 (20), causing the eventual activation of Raf/MAPK kinase/ERK (Raf/MEK/ERK) pathway (21,22). Since nAChRs do not have intrinsic tyrosine kinase activity (3), the molecular mechanisms underlying the proliferative signaling remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Nicotine induces cell proliferation by -arrestin-mediated activation of Src and Rb-Raf-1 pathways

Dasgupta

Rastogi²,

Pillai³

et al. 2006

Journal of Clinical Investigation

276

231

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“…Indeed, suppression of MMP by different inhibitors markedly reduced tumor cell invasiveness and metastasis (23). However, the direct action of nicotine on angiogenesis and invasion of cancer cells remains unknown, although recent studies show that nicotine can regulate endothelial cell growth (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer

Shin¹,

Wu²,

Chu³

et al. 2005

Molecular Cancer Research

103

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Blockade of angiogenesis is a promising strategy to suppress tumor growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF), which binds to tyrosine kinase receptors [VEGF receptors (VEGFR) 1 and 2], is the mediator of angiogenesis and mitogen for endothelial cells. Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of nicotine on gastric cancer growth. However, the action of nicotine and the relationship between COX-2 and VEGF/VEGFR system in tumorigenesis remain undefined. In this study, the effects of nicotine in tumor angiogenesis, invasiveness, and metastasis were studied with sponge implantation and Matrigel membrane models. Nicotine (200 Mg/mL) stimulated gastric cancer cell proliferation, which was blocked by SC-236 (a highly selective COX-2 inhibitor) and CBO-P11 (a VEGFR inhibitor). This was associated with decreased VEGF levels as well as VEGFR-2 but not VEGFR-1 expression. Topical injection of nicotine enhanced tumor-associated vascularization, with a concomitant increase in VEGF levels in sponge implants. Again, application of SC-236 (2 mg/kg) and CBO-P11 (0.4 mg/kg) partially attenuated vascularization by f30%. Furthermore, nicotine enhanced tumor cell invasion through the Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with gastric cancer cells. The activity of matrix metalloproteinases 2 and 9 and protein expressions of plasminogen activators (urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of nicotine on angiogenesis, tumor invasion, and metastasis is COX-2/VEGF/VEGFR dependent. (Mol Cancer Res 2005;3(11):607 -15)

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Nicotine and Cotinine Up-Regulate Vascular Endothelial Growth Factor Expression in Endothelial Cells

Cited by 145 publications

References 35 publications

Nicotine Accelerates Angiogenesis and Wound Healing in Genetically Diabetic Mice

Nicotine Accelerates Angiogenesis and Wound Healing in Genetically Diabetic Mice

Nicotine induces cell proliferation by -arrestin-mediated activation of Src and Rb-Raf-1 pathways

Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer

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