title: Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability.
abstract: Accumulating evidence suggests a pivotal role of the calcitonin receptor-like receptor (CRLR) signaling pathway in preventing damage of the lung by stabilizing pulmonary barrier function. Intermedin (IMD), also termed adrenomedullin-2, is the most recently identified peptide targeting this receptor. Here we investigated the effect of hypoxia on the expression of IMD in the murine lung and cultured murine pulmonary microvascular endothelial cells (PMEC) as well as the role of IMD in regulating vascular permeability. Monoclonal IMD antibodies were generated, and transcript levels were assayed by quantitative RT-PCR. The promoter region of IMD gene was analyzed, and the effect of hypoxia-inducible factor (HIF)-1alpha on IMD expression was investigated in HEK293T cells. Isolated murine lungs and a human lung microvascular endothelial cell monolayer model were used to study the effect of IMD on vascular permeability. IMD was identified as a pulmonary endothelial peptide by immunohistochemistry and RT-PCR. Hypoxia caused an upregulation of IMD mRNA in the murine lung and PMEC. As shown by these results, HIF-1alpha enhances IMD promoter activity. Our functional studies showed that IMD abolished the increase in pressure-induced endothelial permeability. Moreover, IMD decreased basal and thrombin-induced hyperpermeability of an endothelial cell monolayer in a receptor-dependent manner and activated PKA in these cells. In conclusion, IMD is a novel hypoxia-induced gene and a potential interventional agent for the improvement of endothelial barrier function in systemic inflammatory responses and hypoxia-induced vascular leakage.
authors.affiliation: Institute for Anatomy and Cell Biology, Department of Internal Medicine, Justus Liebig University, Aulweg 123, 35385 Giessen, Germany. uwe.pfeil@anatomie.med.uni-giessen.de
authors.forename: Uwe
authors.initials: U
authors.lastname: Pfeil
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.forename: Renate
authors.initials: R
authors.lastname: Paddenberg
authors.forename: Karin
authors.initials: K
authors.lastname: Quanz
authors.forename: Chia L
authors.initials: CL
authors.lastname: Chang
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Park
authors.forename: Barbara
authors.initials: B
authors.lastname: Gries
authors.forename: Amir
authors.initials: A
authors.lastname: Rafiq
authors.forename: Petra
authors.initials: P
authors.lastname: Faulhammer
authors.forename: Anna
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Tamara
authors.initials: T
authors.lastname: Papadakis
authors.forename: Thomas
authors.initials: T
authors.lastname: Noll
authors.forename: Sheau Y T
authors.initials: SY
authors.lastname: Hsu
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015687:Cell Hypoxia; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000166:cytology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D011312:Pressure; D011401:Promoter Regions, Genetic / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C484330:ADM2 protein, human; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D009479:Neuropeptides; D036361:Peptide Hormones; D010455:Peptides; D010750:Phosphoproteins; C514552:intermedin protein, mouse; D000098662:Vasodilator-Stimulated Phosphoprotein; D053607:Adrenomedullin; D010768:Phosphoserine
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