A. Ladoux et C. Frelin, Coordinated up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier, J BIOL CHEM, 275(51), 2000, pp. 39914-39919
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.