ABSTRACT
Although ACTH is important to adrenal growth and steroidogenesis, its role in vascular development and function has not been established in vivo. In the present study, we demonstrate the expression of mRNA for all four VEGF isoforms (mVEGF(120,144,164,188)) and for Flk-1/KDR and Flt-1 receptors in the mouse adrenal in vivo. Suppression of the pituitary adrenocortical axis by dexamethasone (0.5 mg x 100 g body wt(-1) x day(-1) during 6 days) induced a decrease in corticosterone levels, adrenal weights by 50% (P < 0.001), VEGF(188) mRNA, and Flk-1/KDR mRNA, whereas Flt-1 remained consistent during steroid treatment. A daily injection of ACTH-(1-39) restored the transcript for Flk-1/KDR and both VEGF(188) and plasma corticosterone to control levels. To gain further insights into the effects of ACTH, cultured endothelial cells (ECs) were treated with forskolin, which increases cAMP, the second messenger in ACTH action. We demonstrate that Flk-1/KDR protein expression was markedly increased by forskolin within 24-48 h of treatment in a dose-dependent manner (0.1-10 microM). The biological effect of ACTH on ECs was then tested by use of coincubations of fasciculata cells and ECs in 3D-collagen assay. Within 5-7 days of culture, ECs organized into multicellular structures that resemble networks of microvasculature, which characterize angiogenesis in vitro.