Mallet, Christine, Olivier Fé raud, Gaehl OuengueMbé lé , Isabelle Gaillard, Nicolas Sappay, Daniel Vittet, and Isabelle Vilgrain. Differential expression of VEGF receptors in adrenal atrophy induced by dexamethasone: a protective role of ACTH. Am J Physiol Endocrinol Metab 284: E156-E167, 2003; 10.1152/ajpendo.00450.2001.-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 (mVEGF120, 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 ⅐ 100 g body wt Ϫ1 ⅐ day Ϫ1 during 6 days) induced a decrease in corticosterone levels, adrenal weights by 50% (P Ͻ 0.001), VEGF188 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 VEGF188 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 M). 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. vascular endothelial growth factor receptors; adrenocorticotropin; angiogenesis; mouse adrenal; steroidogenesis; hypothalamo-pituitary disconnection; vascular permeability THE ADRENAL CORTEX is physiologically important as the site of formation and secretion of several steroid hormones and less-active steroids. The secreted hormones gain access to the bloodstream through an intense and complex adrenal vasculature that is essential for organ growth and maintenance. The vessels of the adrenal cortex are characterized by richly fenestrated endothelia (2, 40). These fenestrations are the pores through which releasing factors within the hemal milieu can access the cells. In adult mammals, adrenal growth and steroidogenesis are regulated by adrenocorticotropin (ACTH) (27), which acts through interaction with a specific melanocortin receptor (MC2R) specifically expressed in the adrenal cortex (6, 32). This guanine nucleotide-binding protein-coupled receptor elicits the activation of adenylate cyclase and the production of cAMP, which activate the protein kinase A-signaling pathway (39, 53) and the normal functioning of adrenocortical cells. Glucocorticoid hormones are thought to exert negative feedback inhibition on hypothalamic-pituitary-adrenocortical axis activity at the pituitary, hypothalamic, and extrahypothalamic levels. This ultimately results in decreased...