Isoform-specific regulation of vascular endothelial growth factor (VEGF) family mRNA expression in cultured mouse brown adipocytes.

We have shown that brown adipose tissue (BAT), a thermogenic organ in mammals, expresses high levels of vascular endothelial growth factor (VEGF) mRNA in response to exposure to cold, which may contribute to angiogenesis associated with cold-induced hyperplasia of this tissue. In the present study, we examined mRNA expression of not only VEGF, but also VEGF-B and VEGF-C, recently cloned VEGF isoforms, in vitro using immortal brown adipocytes (HB2) isolated from mouse BAT. HB2 preadipocytes expressed detectable levels of VEGF, VEGF-B and VEGF-C mRNA, but a low level of VEGF. After HB2 cells differentiated into adipocytes, the VEGF mRNA level increased without a noticeable change in the VEGF-B and VEGF-C mRNA levels. When HB2 cells were stimulated by norepinephrine, the VEGF mRNA level increased without a change in that of VEGF-B, while the VEGF-C mRNA level decreased. A marked reduction of VEGF-C mRNA expression was also found when HB2 cells were treated with agonists of peroxisome proliferator-activated receptor gamma (PPARgamma, troglitazone), retinoic acid receptor (RAR, all-trans retinoic acid) and retinoid X receptor (RXR, 9-cis retinoic acid). These results suggest a specific adrenergic mechanism for up-regulation of VEGF expression different from those for other VEGF isoforms, and thereby the major contribution of VEGF to the cold-induced angiogenesis in BAT. In addition, the agonists of PPARgamma, RAR and RXR are suggested to be inhibitory to angiogenesis through the reduction of VEGF-C production.