title: Endothelial Msx1 transduces hemodynamic changes into an arteriogenic remodeling response.
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.
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Vandersmissen
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sander
authors.initials: S
authors.lastname: Craps
authors.affiliation: Department of Electrical Engineering/Processing Speech and Images, Medical Image Computing, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Depypere
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Giulia
authors.initials: G
authors.lastname: Coppiello
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Division of Skeletal Tissue Engineering, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Nick
authors.initials: N
authors.lastname: van Gastel
authors.affiliation: Department of Electrical Engineering/Processing Speech and Images, Medical Image Computing, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Maes
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Division of Skeletal Tissue Engineering, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium Department of Materials Engineering, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Schrooten
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Elizabeth A V
authors.initials: EA
authors.lastname: Jones
authors.affiliation: Laboratory of Developmental Signaling, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Leuven, 3000 Leuven, Belgium Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Roland
authors.initials: R
authors.lastname: Devlieger
authors.affiliation: Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.affiliation: Department of Nuclear Medicine University Hospital Leuven, 3000 Leuven, Belgium Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gheysens
authors.affiliation: Laboratory of Developmental Signaling, VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium Hematology and Cell Therapy Area, Clínica Universidad de Navarra and Division of Oncology, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Xabier L
authors.initials: XL
authors.lastname: Aranguren
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium aernout.luttun@med.kuleuven.be.
authors.forename: Aernout
authors.initials: A
authors.lastname: Luttun
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006439:Hemodynamics / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D019485:Bone Morphogenetic Proteins; C090509:Icam1 protein, mouse; D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse; D051785:Smad Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1