Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response

Ine Vandersmissen, Sander Craps, Maarten Depypere, Giulia Coppiello, Nick van Gastel, Frederik Maes, Geert Carmeliet, Jan Schrooten, Elizabeth A V Jones, Lieve Umans, Roland Devlieger, Michel Koole, Olivier Gheysens, An Zwijsen, Xabier L Aranguren, Aernout Luttun

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Collateral remodeling is critical for blood flow restoration in peripheral arterial disease and is triggered by increasing fluid shear stress in preexisting collateral arteries. So far, no arterial-specific mediators of this mechanotransduction response have been identified. We show that muscle segment homeobox 1 (MSX1) acts exclusively in collateral arterial endothelium to transduce the extrinsic shear stimulus into an arteriogenic remodeling response. MSX1 was specifically up-regulated in remodeling collateral arteries. MSX1 induction in collateral endothelial cells (ECs) was shear stress driven and downstream of canonical bone morphogenetic protein-SMAD signaling. Flow recovery and collateral remodeling were significantly blunted in EC-specific Msx1/2 knockout mice. Mechanistically, MSX1 linked the arterial shear stimulus to arteriogenic remodeling by activating the endothelial but not medial layer to a proinflammatory state because EC but not smooth muscle cellMsx1/2 knockout mice had reduced leukocyte recruitment to remodeling collateral arteries. This reduced leukocyte infiltration in EC Msx1/2 knockout mice originated from decreased levels of intercellular adhesion molecule 1 (ICAM1)/vascular cell adhesion molecule 1 (VCAM1), whose expression was also in vitro driven by promoter binding of MSX1.

Original languageEnglish
Pages (from-to)1239-56
Number of pages18
JournalJournal of Cell Biology
Volume210
Issue number7
DOIs
Publication statusPublished - 28 Sep 2015
Externally publishedYes

Keywords

  • Animals
  • Bone Morphogenetic Proteins/genetics
  • Endothelium, Vascular/cytology
  • Hemodynamics/physiology
  • Intercellular Adhesion Molecule-1/genetics
  • MSX1 Transcription Factor/genetics
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular/cytology
  • Signal Transduction/physiology
  • Smad Proteins/genetics
  • Vascular Cell Adhesion Molecule-1/genetics
  • Vascular Remodeling/physiology

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