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Am J Physiol Lung Cell Mol Physiol 297: L837-L845, 2009. First published August 14, 2009; doi:10.1152/ajplung.90608.2008
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Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability

Uwe Pfeil,1 Muhammad Aslam,2 Renate Paddenberg,1 Karin Quanz,3 Chia L. Chang,4 Jae-Il Park,5 Barbara Gries,1 Amir Rafiq,1 Petra Faulhammer,1 Anna Goldenberg,1 Tamara Papadakis,1 Thomas Noll,2 Sheau Y. T. Hsu,6 Norbert Weissmann,3 and Wolfgang Kummer1

1Institute for Anatomy and Cell Biology, ; 2Institute of Physiology, and ; 3Department of Internal Medicine, Justus Liebig University, Giessen, Germany; ; 4Department of Obstetrics and Gynecology, Chang Gung University School of Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan, Republic of China; ; 5Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea; and ; 6Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California

Submitted 9 December 2008 ; accepted in final form 12 August 2009

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)-1{alpha} 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-1{alpha} 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.

endothelial permeability; edema


Address for reprint requests and other correspondence: U. Pfeil, Institute for Anatomy and Cell Biology, Univ. of Giessen Lung Center, Justus-Liebig-Univ., Aulweg 123, 35385 Giessen, Germany (e-mail: uwe.pfeil{at}anatomie.med.uni-giessen.de).






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