Dexamethasone treatment and ICAM-1 deficiency impair VEGF-induced angiogenesis in adult brain.
BACKGROUND
Infusion of exogenous vascular endothelial growth factor (VEGF) into adult brain at doses above 60 ng/day induces dramatic angiogenesis accompanied by vascular leak and inflammation. Blood vessels formed by this treatment are dilated and tortuous, exhibiting a pathological morphology. Pathological VEGF-induced angiogenesis is preceded by vascular leak and inflammation, which have been proposed to mediate subsequent angiogenesis.


METHODS
To test this hypothesis, we infused VEGF into the brains of adult rats to induce pathological angiogenesis. Some of these rats were treated with dexamethasone, a potent anti-inflammatory glucocorticoid, to inhibit inflammation and edema.


RESULTS
We demonstrate that inhibition of inflammation by treatment with dexamethasone significantly attenuated VEGF-induced pathological angiogenesis. To present converging evidence that inflammation may be important in this angiogenic process, we also demonstrate that mice genetically deficient in the inflammatory mediator intercellular adhesion molecule-1 have attenuated VEGF-induced angiogenesis. These same mice showed normal amounts of physiological angiogenesis in response to enriched environments, however, suggesting that a generalized reduction in vascular plasticity could not account for their poor angiogenic response to VEGF.


CONCLUSIONS
Taken together, the data from these experiments suggest that the inflammation which occurs before or during VEGF-induced pathological brain angiogenesis plays a contributory role in the pathological angiogenic process.
Kasselman
Lora J
LJ
Neuropsychology Doctoral Subprogram, Graduate Center of the City University of New York, NY, USA.
Kintner
Jennifer
J
Sideris
Alexandra
A
Pasnikowski
Elizabeth
E
Krellman
Jason W
JW
Shah
Sagar
S
Rudge
John S
JS
Yancopoulos
George D
GD
Wiegand
Stanley J
SJ
Croll
Susan D
SD
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000276:immunology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D005938:Glucocorticoids; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone