In vivo imaging of bone marrow endothelial dysfunction promoting myeloid cell expansion in cardiovascular disease
Katrien Vandoorne1,2, I-Hsiu Lee1, Jana Grune1, Shuang Zhang1, Cameron S. McAlpine1, Maximilian J. Schloss1, Ribhu Nayar1, Gabriel Courties1, Vanessa Frodermann1, Gregory Wojtkiewicz1, Lisa Honold1, Qi Chen3, Yoshiko Iwamoto1, Yuan Sun1, Sebastian Cremer1, Oriol Iborra-Egea4, Christian Munoz-Guijosa4, Fei Ji5, Bin Zhou6, Ralf H. Adams3, Joshua D. Wythe7, Juan Hidalgo8, Hideto Watanabe9, Yookyung Jung10, Anja van der Laan11, Jan J. Piek11, Youmna Kfoury12,13, Pauline A. Désogère14, Claudio Vinegoni1, Partha Dutta15, Ruslan I. Sadreyev5,16, Peter Caravan14, Antoni Bayes-Genis4, Peter Libby17, David T. Scadden12,13, Charles P. Lin1,9, Kamila Naxerova1, Filip K Swirski1, Matthias Nahrendorf1, and David Rohde1,18
1Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States, 2Biomedical Engineering, Technion, Israel Institute of Technology, Haifa, Israel, 3Max Planck Institute for Molecular Biomedicine, Muenster, Germany, 4Institut del Cor Germans Trias i Pujol, Barcelona, Spain, 5Genetics, Harvard Medical School, Boston, MA, United States, 6State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academic of Sciences, Shanghai, China, 7Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States, 8Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain, 9Institute for Molecular Science of Medicine, Aichi Medical University, Aichi, Japan, 10Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States, 11Heart Center, Department of Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Amsterdam, Netherlands, 12Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA, United States, 13Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, United States, 14Martinos Center for Biomedical Imaging, Department of Radiolog, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States, 15Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States, 16Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States, 17Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States, 18Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Heidelberg, Germany
Hematopoietic stem cells at the bone marrow (BM) niche generates excess inflammatory leukocytes harming the heart after a myocardial infarction (MI). Whether MI affects the hematopoietic organ’s microvasculature is unknown. Here intravital microscopy shows that MI triggers endothelial dysfunction, leakage, and angiogenesis in the BM, leading to systemic leukocytosis. These novel findings were imaged by noninvasive PET imaging of integrin αVβ3 activation concomitant with measuring leakiness using dynamic contrast enhanced MRI. Endothelial deletion of Vegf receptor 2 (Vegfr2) curbed emergency hematopoiesis after MI. Our findings establish that MI remodels the vascular BM niche, stimulating hematopoiesis and production of inflammatory leukocytes.
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