Paracrine control of the adult adrenal cortex vasculature by vascular endothelial growth factor

The extensive vascular network that irrigates the adult adrenal cortex is essential for both the delivery of oxygen and nutrients to glandular steroidogenic cells and for the rapid and efficient export of corticosteroid products from these cells into the blood flow. During experimental and pathological changes in adrenal cortex size caused by ACTH overproduction or deficiency, the vasculature evolves in a coordinated manner with the mass of glandular cells so that blood vessel formation/regression and cortical gowth/atrophy are respectively synchronized. In addition to its previously reported expression in human fetal adrenocortical cells, the angiogenic factor VEGF-A appears also to be strongly expressed by both glomerulosa and fasciculata cells of the adult bovine adrenal cortex, when the endothelium is quiescent. Moreover, the expression of the two major transcripts encoding the 121 and the 165 amino acid-long isoforms of VEGF-A was observed to be rapidly (within 2-4 h) up-regulated (2-3 fold) by ACTH in primary cultures of bovine fasciculata and glomerulosa cells. The expression of the signalling VEGF receptors R1 (flt-1) and R2 (flk-1) was restricted to the endothelial cells of the cortex whereas neuropilin-1 was expressed by both endothelial and steroidogenic cells. This suggests that, under the control of the pituitary hormone ACTH, VEGF exerts a paracrine control over the vasculature of the adult adrenal cortex. Given its known effects as an anti-apoptotic agent and an inducer of endothelial fenestration, VEGF is likely to play a role in the maintenance of the dense and fenestrated vascular bed of the adrenal cortex. The vasculature thus appears as an important secondary target of ACTH action in the physiological control of adrenal cortex homeostasis.