Coordinated up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier

Adrenomedullin (ADM) is a potent hypotensive peptide, which is produced dur ing sepsis and ischemia. We demonstrate here that hypoxia induced a time-de pendent increase of both ADM mRNA and protein expressions in cultured astro cytes and endothelial cells from rat brain microvessels. Gene reporter anal yses showed a 2-fold increase in ADM gene transcription which was suppresse d when the ADM promoter was deleted of its hypoxia responsive element. Hypo xia increased 7-fold the stability of pre-formed ADM mRNAs. Rat brain micro vessels expressed mRNAs coding for the different putative ADM receptors but they did not respond to exogenous ADM and calcitonin gene-related peptide by the formation of cAMP. In contrast, ADM and calcitonin gene-related pept ide increased the formation of cAMP in astrocytes and their actions were po tentiated about 2-fold after hypoxia. Messenger RNA species coding for thre e putative ADM receptors (the L1 orphan receptor, RDC-1, and calcitonin rec eptor-like receptor) and accessory proteins (receptor-activity modifying pr oteins) were present in astrocytes. Hypoxia selectively up-regulated expres sion of RDC-1 receptor mRNAs. The results indicate that ADM and RDC-1 are h ypoxia-sensitive genes and that RDC-1 receptors may mediate some actions of ADM in hypoxic astrocytes.