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 during sepsis and ischemia. We demonstrate here that hypoxia induced a time-dependent increase of both ADM mRNA and protein expressions in cultured astrocytes and endothelial cells from rat brain microvessels. Gene reporter analyses showed a 2-fold increase in ADM gene transcription which was suppressed when the ADM promoter was deleted of its hypoxia responsive element. Hypoxia increased 7-fold the stability of pre-formed ADM mRNAs. Rat brain microvessels 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 peptide increased the formation of cAMP in astrocytes and their actions were potentiated about 2-fold after hypoxia. Messenger RNA species coding for three putative ADM receptors (the L1 orphan receptor, RDC-1, and calcitonin receptor-like receptor) and accessory proteins (receptor-activity modifying proteins) were present in astrocytes. Hypoxia selectively up-regulated expression of RDC-1 receptor mRNAs. The results indicate that ADM and RDC-1 are hypoxia-sensitive genes and that RDC-1 receptors may mediate some actions of ADM in hypoxic astrocytes.
Ladoux
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A
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UPR 411, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. ladoux@ipmc.cnrs.fr
Frelin
C
C
D053607:Adrenomedullin; D000818:Animals; D001483:Base Sequence; D001812:Blood-Brain Barrier; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017931:DNA Primers; D016228:Endothelial Growth Factors / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000235:genetics*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017931:DNA Primers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010455:Peptides; D012333:RNA, Messenger; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D053607:Adrenomedullin