Ets-1 Is a Critical Regulator of Ang II-mediated Vascular Inflammation and Remodeling

J Clin Invest. 2005 Sep;115(9):2508-16. doi: 10.1172/JCI24403.

Abstract

Ang II is a central mediator of vascular inflammation and remodeling. The transcription factor Ets-1 is rapidly induced in vascular smooth muscle and endothelial cells of the mouse thoracic aorta in response to systemic Ang II infusion. Arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1-/- mice compared with control mice in response to Ang II. The induction of 2 known targets of Ets-1, cyclin-dependent kinase inhibitor p21CIP and plasminogen activator inhibitor-1 (PAI-1), by Ang II is markedly blunted in the aorta of Ets1-/- mice compared with wild-type controls. Expression of p21CIP in VSMCs leads to cellular hypertrophy, whereas expression of p21CIP in endothelial cells is associated with cell cycle arrest, apoptosis, and endothelial dysfunction. PAI-1 promotes the development of perivascular fibrosis. We have identified monocyte chemoattractant protein-1 (MCP-1) as a novel target for Ets-1. Expression of MCP-1 is similarly reduced in Ets1-/- mice compared with control mice in response to Ang II, which results in significantly diminished recruitment of T cells and macrophages to the vessel wall. In summary, our results support a critical role for Ets-1 as a transcriptional mediator of vascular inflammation and remodeling in response to Ang II.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / metabolism*
  • Animals
  • Aorta* / anatomy & histology
  • Aorta* / immunology
  • Aorta* / metabolism
  • Aorta* / pathology
  • Blood Pressure
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • Gene Expression Regulation
  • Humans
  • Inflammation / metabolism*
  • Interleukin-6 / metabolism
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Protein c-ets-1 / metabolism*
  • Tissue Plasminogen Activator / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Ccl2 protein, mouse
  • Cdkn1a protein, mouse
  • Chemokine CCL2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Ets1 protein, mouse
  • Interleukin-6
  • Klf5 protein, mouse
  • Kruppel-Like Transcription Factors
  • Plasminogen Activator Inhibitor 1
  • Proto-Oncogene Protein c-ets-1
  • Vascular Cell Adhesion Molecule-1
  • Angiotensin II
  • Tissue Plasminogen Activator