Nicotine increases size and severity of experimental choroidal neovascularization.
OBJECTIVE
Cigarette smoking is the strongest environmental risk factor for all forms of age-related macular degeneration (AMD). In the present study, the influence of nicotine on the severity of choroidal neovascularization (CNV) in a mouse model of neovascular AMD and its effects on vascular smooth muscle cells derived from mouse choroid were investigated.


METHODS
A mouse model for CNV was used to study the effects of nicotine in young and middle-aged mice. Nicotine was administered orally in the drinking water to achieve serum levels consistent with those of chronic smokers. Hexamethonium, a nonspecific nicotinic receptor antagonist, was injected subconjunctivally to counteract the effects of nicotine. A mouse choroidal vascular smooth muscle cell line was exposed to nicotine, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), or a combination of one of the factors and nicotine. Cell growth was determined by cell counts, and the activity of matrix metalloproteinase (MMP)-2 and -9 was quantified by gel zymography.


RESULTS
Nicotine administration resulted in increased size and vascularity of CNV, and older mice developed a greater relative increase than younger mice. This effect was blocked by subconjunctival hexamethonium. Choroidal vascular smooth muscle cells demonstrated a statistically significant increase in growth after exposure to a combination of PDGF and nicotine. Nicotine also reversed VEGF-induced suppression of MMP-2 activity.


CONCLUSIONS
Nicotine increases size and severity of experimental CNV in the present mouse model, possibly by potentiating PDGF-mediated upregulation of proliferation of choroidal smooth muscle cells or by other mechanisms. These results suggest that non-neuronal nicotinic receptor activation probably mediates some of the harmful effects of cigarette smoking in wet AMD.
Suñer
Ivan J
IJ
Department of Ophthalmology, Miami Veterans Affairs Medical Center, Miami, Florida, USA. isuner@med.miami.edu
Espinosa-Heidmann
Diego G
DG
Marin-Castano
Maria E
ME
Hernandez
Eleut P
EP
Pereira-Simon
Simone
S
Cousins
Scott W
SW
D000284:Administration, Oral; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002829:Choroid / Q000098:blood supply / Q000187:drug effects*; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D005451:Fluorescein Angiography; D018738:Hexamethonium / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D004338:Drug Combinations; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D018738:Hexamethonium; D009538:Nicotine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9