Vascular injury triggers Krüppel-like factor 6 mobilization and cooperation with specificity protein 1 to promote endothelial activation through upregulation of the activin receptor-like kinase 1 gene

Eva M. Garrido-Martín, Francisco J. Blanco, Mercé Roquè, Laura Novensà, Mirko Tarocchi, Ursula E. Lang, Toru Suzuki, Scott L. Friedman, Luisa M. Botella, Carmelo Bernabéu

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Rationale: Activin receptor-like kinase-1 (ALK1) is an endothelial transforming growth factor β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic stimuli such as vascular injury. Objective: To characterize the molecular mechanisms underlying the regulation of ALK1 on vascular injury. Methods and Results: Alk1 becomes strongly upregulated in endothelial (EC) and vascular smooth muscle cells of mouse femoral arteries after wire-induced endothelial denudation. In vitro denudation of monolayers of human umbilical vein ECs also leads to an increase in ALK1. Interestingly, a key factor in tissue remodeling, Krüppellike factor 6 (KLF6) translocates to the cell nucleus during wound healing, concomitantly with an increase in the ALK1 gene transcriptional rate. KLF6 knock down in human umbilical vein ECs promotes ALK1 mRNA downregulation. Moreover, Klf6+/- mice have lower levels of Alk1 in their vasculature compared with their wildtype siblings. Chromatin immunoprecipitation assays show that KLF6 interacts with ALK1 promoter in ECs, and this interaction is enhanced during wound healing. We demonstrate that KLF6 is transactivating ALK1 gene, and this transactivation occurs by a synergistic cooperative mechanism with specificity protein 1. Finally, Alk1 levels in vascular smooth muscle cells are not directly upregulated in response to damage, but in response to soluble factors, such as interleukin 6, released from ECs after injury. Conclusions: ALK1 is upregulated in ECs during vascular injury by a synergistic cooperative mechanism between KLF6 and specificity protein 1, and in vascular smooth muscle cells by an EC-vascular smooth muscle cell paracrine communication during vascular remodeling.

Original languageEnglish
Pages (from-to)113-127
Number of pages15
JournalCirculation Research
Volume112
Issue number1
DOIs
StatePublished - 10 Oct 2012

Keywords

  • Activin receptor-like kinase 1
  • Cell culture
  • Endothelial cell
  • Hereditary hemorrhagic telangiectasia
  • Krüppel-like factor 6
  • Smooth muscle cell
  • Vascular injury

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