Adipose tissue is highly vascularized implying that angiogenesis takes place in its expansion. The aim of this study was to compare the concentrations of members of the vascular endothelial growth factor (VEGF) family in obesity. Serum concentrations of VEGFs were analyzed in 15 lean (BMI 20.3+/-2.5 kg/m(2)) and 24 obese (BMI 47.6+/-5.9 kg/m(2)) volunteers. Obese patients showed significantly increased circulating VEGF-A (150+/-104 vs. 296+/-160 pg/ml; P<.05), VEGF-B (2788+/-1038 vs. 4609+/-2202 arbitrary units; P<.05) and VEGF-C (13 453+/-5750 vs. 17 635+/-5117 pg/ml; P<.05) concentrations. Interestingly, levels of VEGF-D were reduced in obese individuals (538+/-301 vs. 270+/-122 pg/ml; P<.01). In addition, VEGF-A significantly decreased after weight loss following Roux-en-Y gastric bypass (BMI from 46.0+/-8.0 to 28.9+/-4.2 kg/m(2)P<.0001 vs. initial) from 345+/-229 to 290+/-216 pg/ml (P<.01). Moreover, in order to corroborate the human findings VEGF-A levels were analyzed during the expansion of adipose tissue in two dynamic models of murine obesity. Serum VEGF-A was significantly increased after 12 weeks on a high-fat diet (43.3+/-9.0 vs. 29.7+/-9.1 pg/ml; P<.01) or in ob/ob mice (52.2+/-18.0 vs. 29.2+/-7.7 pg/ml; P<.01) and was normalized after leptin replacement in the latter (32.4+/-14.0 pg/ml; P<.01 vs. untreated ob/ob). Our data indicates the involvement of these factors in the expansion of adipose tissue that takes place in obesity in relation to the need for increased vascularization, suggesting that manipulation of the VEGF system may represent a potential target for the pharmacological treatment of obesity.