Aspirin inhibits endothelial nitric oxide synthase (eNOS) and Flk-1 (vascular endothelial growth factor receptor-2) prior to rat colon tumour development.
Formation of blood vessels is a fundamental element in the control of tumour growth in which vascular endothelial growth factor (VEGF) and nitric oxide (NO) have been demonstrated to be involved. Our aim was to analyse whether changes in the expression of endothelial NO synthase (eNOS) and VEGF in colonic tissue could be detected early and even before the identification of colon tumour-associated morphological modifications in azoxymethane-treated rats. We studied further whether aspirin treatment changed these parameters. An increased expression of both eNOS and VEGF in colonic tissue from azoxymethane-treated rats compared with that from control rats was found. Aspirin treatment (10 mg/kg of body weight per day) reduced eNOS expression, but failed to modify the expression of VEGF in the colonic tissue of azoxymethane-treated rats. No evidence of aberrant crypt formation or changes in the number of blood vessels were observed in the colon of any of the animals studied. Expression of the VEGF receptor Flk-1, but not Flt-1, was increased in colonic tissue of azoxymethane-treated rats compared with control rats. The expression of Flk-1 was mainly localized in the epithelial cells, particularly in the lower part of the crypt. Aspirin treatment reduced Flk-1 expression in both control and azoxymethane-treated rats. Caspase-3 activity, which has been considered as an apoptotic index, was almost undetectable in azoxymethane-treated rats. Aspirin treatment stimulated caspase-3 activity. Overexpression of eNOS, VEGF and its receptor Flk-1 occurred early after azoxymethane administration in rat colonic tissue, even before morphological changes associated with tumour generation were observed, and aspirin prevented the overexpression of both eNOS and VEGF receptor Flk-1.
Escribano
Marta
M
Digestive Research Laboratory, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain.
Molero
Laura
L
López-Farré
Antonio
A
Abarrategui
Cynthia
C
Carrasco
Carolina
C
García-Mendez
Antonio
A
Manzarbeitia
Félix
F
Martín
María Jesús
MJ
Vázquez
Marian
M
Sánchez-Fayos
Paloma
P
Rico
Luis
L
Porres Cubero
Juan Carlos
JC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology*; D001397:Azoxymethane; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003106:Colon / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D011921:Rats, Inbred WKY; D012039:Regional Blood Flow; D015854:Up-Regulation / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D001397:Azoxymethane; D001241:Aspirin