Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling
Yumei Zhan, … , I-Cheng Ho, Peter Oettgen
Yumei Zhan, … , I-Cheng Ho, Peter Oettgen
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2508-2516. https://doi.org/10.1172/JCI24403.
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Research Article Vascular biology

Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling

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.

Authors

Yumei Zhan, Courtney Brown, Elizabeth Maynard, Aleksandra Anshelevich, Weihua Ni, I-Cheng Ho, Peter Oettgen

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Figure 1

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In vivo induction of Ets-1 in response to Ang II and altered vascular re...
In vivo induction of Ets-1 in response to Ang II and altered vascular remodeling in Ets1–/– mice. (A) Ets-1 expression as measured by quantitative RT-PCR in the thoracic aorta of C57BL/6 mice, 3 days and 2 weeks after Ang II infusion (1.4 mg/kg/d). Values are expressed as fold induction compared with sham-treated controls. (B) Immunohistochemical analysis of Ets-1 expression after infusion of Ang II for 2 weeks in C57BL/6 mice compared with sham-treated controls. L, lumen. Original magnification, ×200. (C) Comparison of the effects of Ang II infusion and sham treatment on perivascular fibrosis and arterial thickening in the aorta of Ets1+/+ versus Ets1–/– mice. Aortic sections were stained with Masson trichrome stain. Original magnification, ×20 (left) and ×100 (right). (D) Analysis of medial thickness and medial area/lumen area ratio (left) and perivascular fibrosis thickness and fibrosis area/vessel area ratio (right) in Ets1+/+ versus Ets1–/– mice compared with sham-treated controls. (E) Comparison of the effect of Ang II infusion versus sham treatment on renal artery hypertrophy in Ets1+/+ versus Ets1–/– mice. Sections were stained with H&E. (F) Statistical analysis of medial thickness of the renal arteries in Ets1+/+ versus Ets1–/– mice compared with sham-treated controls. *P < 0.01 versus corresponding sham-treated control; †P < 0.01 versus corresponding Ets1+/+ mice that underwent Ang II infusion. Values represent mean ± SEM; n = 5.