title: Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension.
abstract: Various hypertensive stimuli lead to exuberant adventitial collagen deposition in large arteries, exacerbating blood pressure elevation and end-organ damage. Collagen production is generally attributed to resident fibroblasts; however, other cells, including resident and bone marrow-derived stem cell antigen positive (Sca-1(+)) cells and endothelial and vascular smooth muscle cells, can produce collagen and contribute to vascular stiffening. Using flow cytometry and immunofluorescence, we found that adventitial Sca-1(+) progenitor cells begin to produce collagen and acquire a fibroblast-like phenotype in hypertension. We also found that bone marrow-derived cells represent more than half of the matrix-producing cells in hypertension, and that one-third of these are Sca-1(+). Cell sorting and lineage-tracing studies showed that cells of endothelial origin contribute to no more than one fourth of adventitial collagen I(+) cells, whereas those of vascular smooth muscle lineage do not contribute. Our findings indicate that Sca-1(+) progenitor cells and bone marrow-derived infiltrating fibrocytes are major sources of arterial fibrosis in hypertension. Endothelial to mesenchymal transition likely also contributes, albeit to a lesser extent and pre-existing resident fibroblasts represent a minority of aortic collagen-producing cells in hypertension. This study shows that vascular stiffening represents a complex process involving recruitment and transformation of multiple cells types that ultimately elaborate adventitial extracellular matrix.
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Kim Ramil C
authors.initials: KR
authors.lastname: Montaniel
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Jay D
authors.initials: JD
authors.lastname: Humphrey
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Majesky
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: David T
authors.initials: DT
authors.lastname: Paik
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Hatzopoulos
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.).
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine (J.W., K.R.C.M., M.A.S., L.X., W.C., M.S.M., D.G.H.), Department of Molecular Physiology and Biophysics (K.R.C.M., M.S.M., D.G.H.), Division of Cardiovascular Medicine, Department of Medicine (D.T.P., A.K.H.), and Department of Cell and Developmental Biology (D.T.P., A.K.H.), School of Medicine, Vanderbilt University, Nashville, TN; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt (M.A.S.); Robert M. Berne Cardiovascular Research Center, Department of Physiology, University of Virginia, Charlottesville (G.K.O.); Department of Biomedical Engineering, Yale University, New Haven, CT (J.D.H.); Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT (J.D.H.); Seattle Children's Research Institute, WA (M.W.M.). david.g.harrison@vanderbilt.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology
chemical_list: D016326:Extracellular Matrix Proteins; D003094:Collagen
keywords: adventitia; aorta; flow cytometer; hypertension; inflammation