title: Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature-a role of β1-integrin in progenitor cell migration and adhesion.
abstract: Hyperhomocysteinemia (HHcy) impairs re-endothelialization and accelerates vascular remodeling. The role of CD34(+)/VEGF receptor (VEGFR) 2(+) progenitor cells (PCs) in vascular repair in HHcy is unknown. We studied the effect of HHcy on PCs and its role in vascular repair in severe HHcy (∼150 μM), which was induced in cystathionine-β synthase heterozygous mice fed a high-methionine diet for 8 weeks. Vascular injury was introduced by carotid air-dry endothelium denudation. CD34(+)/VEGFR2(+) cells were examined by flow cytometry. HHcy reduced bone marrow (BM) CD34(+)/VEGFR2(+) cells and suppressed replenishment of postinjury CD34(+)/VEGFR2(+) cells in peripheral blood (PB). Donor green fluorescent protein-positive PC homing to the injured vessel was reduced in HHcy after CD34(+) PCs from enhanced green fluorescent protein mice were adoptively transferred following carotid injury. CD34(+) PC transfusion partially reversed HHcy-suppressed re-endothelialization and HHcy-induced neointimal formation. Furthermore, homocysteine (Hcy) inhibited proliferation, adhesion, and migration and suppressed β1-integrin expression and activity in human CD34(+) endothelial colony-forming cells (ECFCs) isolated from PBs in a dose-dependent manner. A functional-activating β1-integrin antibody rescued Hcy-suppressed adhesion and migration in CD34(+) ECFCs. In conclusion, HHcy reduces BM CD34(+)/VEGFR2(+) generation and suppresses CD34(+)/VEGFR2(+) cell mobilization and homing to the injured vessel via β1-integrin inhibition, which partially contributes to impaired re-endothelialization and vascular remodeling.
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Jun
authors: J
authors: Nelson
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Yi
authors: Y
authors: Wu
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Xiaohua
authors: X
authors: Jiang
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Remus
authors: R
authors: Berretta
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Steven
authors: S
authors: Houser
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Eric
authors: E
authors: Choi
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Jingfeng
authors: J
authors: Wang
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Jian
authors: J
authors: Huang
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Xiaofeng
authors: X
authors: Yang
authors: *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA hongw@temple.edu.
authors: Hong
authors: H
authors: Wang
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology* / Q000502:physiology*; D020212:Carotid Artery Injuries / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion; D002465:Cell Movement; D003114:Colony-Forming Units Assay; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D019012:Integrin beta1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058426:Neointima / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D066253:Vascular Remodeling
chemical_list: D018952:Antigens, CD34; D019012:Integrin beta1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C000588866:KDR protein, human; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D003541:Cystathionine beta-Synthase
keywords: cell therapy; endothelial repair; vascular remodeling