Obstruction of Small Arterioles in Patients with Critical Limb Ischemia due to Partial Endothelial-to-Mesenchymal Transition
Jacqueline Chevalier,
Hao Yin,
John-Michael Arpino,
Caroline O'Neil,
Zengxuan Nong,
Kevin J. Gilmore,
Jason J. Lee,
Emma Prescott,
Matthew Hewak,
Charles L. Rice,
Luc Dubois,
Adam H. Power,
Douglas W. Hamilton,
J. Geoffrey Pickering
Affiliations
Jacqueline Chevalier
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Canada
Hao Yin
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada
John-Michael Arpino
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Canada
Caroline O'Neil
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada
Zengxuan Nong
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada
Kevin J. Gilmore
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Canada; School of Kinesiology, Faculty of Health Sciences, Western University, London, Canada
Jason J. Lee
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Canada
Emma Prescott
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Canada
Matthew Hewak
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Canada
Charles L. Rice
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Canada; School of Kinesiology, Faculty of Health Sciences, Western University, London, Canada
Luc Dubois
Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, Canada
Adam H. Power
Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, Canada
Douglas W. Hamilton
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Canada
J. Geoffrey Pickering
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Canada; Corresponding author
Summary: Critical limb ischemia (CLI) is a hazardous manifestation of atherosclerosis and treatment failure is common. Abnormalities in the arterioles might underlie this failure but the cellular pathobiology of microvessels in CLI is poorly understood. We analyzed 349 intramuscular arterioles in lower limb specimens from individuals with and without CLI. Arteriolar densities were 1.8-fold higher in CLI muscles. However, 33% of small (<20 μm) arterioles were stenotic and 9% were completely occluded. The lumens were closed by bulky, re-oriented endothelial cells expressing abundant N-cadherin that uniquely localized between adjacent and opposing endothelial cells. S100A4 and SNAIL1 were also expressed, supporting an endothelial-to-mesenchymal transition. SMAD2/3 was activated in occlusive endothelial cells and TGFβ1 was increased in the adjacent mural cells. These findings identify a microvascular closure process based on mesenchymal transitions in a hyper-TGFß environment that may, in part, explain the limited success of peripheral artery revascularization procedures.
