title: A novel role of endothelium in activation of latent pro-membrane type 1 MMP and pro-MMP-2 in rat aorta.
abstract: OBJECTIVE
  Aortic stiffness is an independent risk factor for progression of cardiovascular diseases. Degradation of elastic fibres in aorta due to angiotensin II (ANGII)-stimulated overactivation of latent membrane type 1 matrix metalloproteinase (MT1MMP) and matrix metalloproteinase-2 (MMP2) is regarded to represent an important cause of aortic stiffness. Therefore, clarification of the causal mechanisms triggering the overactivation of these MMPs is of utmost importance. This study addresses the endothelium as a novel key activator of latent pro-MT1MMP and pro-MMP2 in rat aorta.
  
  
  RESULTS
  Using a co-culture model of rat aortic endothelial cells (ECs) and smooth muscle cells (SMCs), we found that ANGII stimulation resulted in activation of latent pro-MT1MMP and pro-MMP2 in SMCs exclusively when co-cultured with ECs (assessed with western blot and gelatin zymography, respectively). EC-specific AT1 receptor stimulation triggered endothelin-1 release and paracrine action on SMCs. Endothelin-1 increased expression and activity of pro-protein convertase furin in SMCs via endothelin receptor type A (assessed with qPCR and furin activity assay, respectively). Consequently, furin acted in two ways. First, it increased the activation of latent pro-MT1MMP and, second, it activated pro-αvβ3 integrin. Both pathways led to overactivation of latent pro-MMP2. In vitro findings in the co-culture model were fully consistent with the ex vivo findings obtained in isolated rat aorta.
  
  
  CONCLUSIONS
  We propose that the endothelium under ANGII stimulation acts as a novel and key activator of latent pro-MT1MMP and pro-MMP2 in SMCs of rat aorta. Therefore, endothelium may critically contribute to pathophysiology of aortic stiffness.
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Otto
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany andreas.deussen@tu-dresden.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Deussen
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Zatschler
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Müller
authors.affiliation: Department of Anatomy, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Neisser
authors.affiliation: Department of Anatomy, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Barth
authors.affiliation: Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University, Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Morawietz
authors.affiliation: Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Germany.
authors.forename: Irakli
authors.initials: I
authors.lastname: Kopaliani
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051381:Rats
chemical_list: D019332:Endothelin-1; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D053511:Matrix Metalloproteinase 14
keywords: Angiotensin II; Endothelin-1; Endothelium; MMPs; Smooth muscle cell