Adrenomedullin Reduces Endothelial Hyperpermeability

• Published in: Circulation research 2002-10, Vol.91 (7), p.618-625
• Main Authors: Hippenstiel, Stefan, Witzenrath, Martin, Schmeck, Bernd, Hocke, Andreas, Krisp, Mathias, Krüll, Matthias, Seybold, Joachim, Seeger, Werner, Rascher, Wolfgang, Schütte, Hartwig, Suttorp, Norbert
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - drug effects; Actin Cytoskeleton - ultrastructure; Adrenomedullin; Animals; Biological and medical sciences; Blood vessels and receptors; Calcium - analysis; Cell Membrane Permeability; Cells, Cultured; Cyclic AMP - biosynthesis; Cyclic GMP - biosynthesis; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiology; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen Peroxide - antagonists & inhibitors; Lung - blood supply; Lung - metabolism; Myosin Light Chains - metabolism; Peptides - metabolism; Peptides - pharmacology; Phosphorylation; Pulmonary Edema - etiology; Rabbits; Swine; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000036603.61868.F9

ABSTRACT—Endothelial hyperpermeability induced by inflammatory mediators is a hallmark of sepsis and adult respiratory distress syndrome. Increased levels of the regulatory peptide adrenomedullin (ADM) have been found in patients with systemic inflammatory response. We analyzed the effect of ADM on the permeability of cultured human umbilical vein endothelial cell (HUVEC) and porcine pulmonary artery endothelial cell monolayers. ADM dose-dependently reduced endothelial hyperpermeability induced by hydrogen peroxide (H2O2), thrombin, and Escherichia coli hemolysin. Moreover, ADM pretreatment blocked H2O2-related edema formation in isolated perfused rabbit lungs and increased cAMP levels in lung perfusate. ADM bound specifically to HUVECs and porcine pulmonary artery endothelial cells and increased cellular cAMP levels. Simultaneous inhibition of cAMP-degrading phosphodiesterase isoenzymes 3 and 4 potentiated ADM-dependent cAMP accumulation and synergistically enhanced ADM-dependent reduction of thrombin-induced hyperpermeability. However, ADM showed no effect on endothelial cGMP content, basal intracellular Ca levels, or the H2O2-stimulated, thrombin-stimulated, or Escherichia coli hemolysin–stimulated Ca increase. ADM diminished thrombin- and H2O2-related myosin light chain phosphorylation as well as stimulus-dependent stress fiber formation and gap formation in HUVECs, suggesting that ADM may stabilize the barrier function by cAMP-dependent relaxation of the microfilament system. These findings identify a new function of ADM and point to ADM as a potential interventional agent for the reduction of vascular leakage in sepsis and adult respiratory distress syndrome.