Essential role of Smad3 in angiotensin II-induced vascular fibrosis

Wansheng Wang, Xiao R. Huang, Ellery Canlas, Kazuhiro Oka, Luan Truong, Chuxia Deng, Neil A. Bhowmick, Wenjun Ju, Erwin P. Bottinger, Hui Y. Lan

Research output: Contribution to journalArticle

175 Scopus citations

Abstract

Angiotensin II (Ang II) plays a pivotal role in vascular fibrosis, which leads to serious complications in hypertension and diabetes. However, the underlying signaling mechanisms are largely unclear. In hypertensive patients, we found that arteriosclerosis was associated with the activation of Smad2/3. This observation was further investigated in vitro by stimulating mouse primary aorta vascular smooth muscle cells (VSMCs) with Ang II. There were several novel findings. First, Ang II was able to activate an early Smad signaling pathway directly at 15 to 30 minutes. This was extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) dependent but transforming growth factor-β (TGF-β) independent because Ang II-induced Smad signaling was blocked by addition of ERK1/2 inhibitor and by dominant-negative (DN) ERK1/2 but not by DN-TGF-β receptor II (TβRII) or conditional deletion of TβRII. Second, Ang II was also able to activate the late Smad2/3 signaling pathway at 24 hours, which was TGF-β dependent because it was blocked by the anti-TGF-β antibody and DN-TβRII. Finally, activation of Smad3 but not Smad2 was a key and necessary mechanism of Ang II-induced vascular fibrosis because Ang II induced Smad3/4 promoter activities and collagen matrix expression was abolished in VSMCs null for Smad3 but not Smad2. Thus, we concluded that Ang II induces vascular fibrosis via both TGF-β-dependent and ERK1/2 MAPK-dependent Smad signaling pathways. Activation of Smad3 but not Smad2 is a key mechanism by which Ang II mediates arteriosclerosis.

Original languageEnglish (US)
Pages (from-to)1032-1039
Number of pages8
JournalCirculation Research
Volume98
Issue number8
DOIs
StatePublished - Apr 2006

Keywords

  • Angiotensin
  • Smads
  • TGF-β
  • Vascular fibrosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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