title: High flow drives vascular endothelial cell proliferation during flow-induced arterial remodeling associated with the expression of vascular endothelial growth factor.
abstract: Endothelial cell activation and proliferation are the essential steps in flow-induced arterial remodeling. We investigated endothelial cell turnover in the early stages of high-flow in the rabbit common carotid arteries using an arteriovenous fistula (AVF) model by kinetic investigation of cell proliferation and cell molecular analysis. BrdU was administrated to label endothelial cells (ECs) in DNA synthetic phase (S-phase) of the cell mitotic cycle. Pulse labeling revealed that ECs entered S-phase at 1.5 days of AVF (0.93 +/- 0.19%). Endothelial cell labeling index (EC-LI) peaked at 2 days of AVF (8.90 +/- 0.87%) with a high index of endothelial cell mitosis (EC-MI, 1.67 +/- 0.47%). Endothelial cell density increased remarkably at 3 days of AVF with a significant decrease in EC-LI (54%) and EC-MI (60%). Study of kinetics of EC proliferation revealed that endothelial cells took 16-24 h to finish one cycle of cell mitosis. Tracking investigation of pulse BrdU-labeled endothelial cells at 1.5 days showed that more than 66% of endothelial cells were BrdU-labeled 1.5 days after labeling. VEGF, integrin alphanubeta3, PECAM-1, and VE-cadherin were upregulated significantly preceding endothelial cell proliferation and kept at high levels during endothelial cell proliferation. These data suggest that endothelial cell proliferation is the initial step in flow-induced arterial remodeling. Hemodynamic forces may drive endothelial cell downstream migration. Expression of VEGF and cell junction molecules contribute to flow-induced arterial remodeling.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305-5642, USA. isho@stanford.edu
authors.forename: Eiketsu
authors.initials: E
authors.lastname: Sho
authors.forename: Masayo
authors.initials: M
authors.lastname: Komatsu
authors.forename: Mien
authors.initials: M
authors.lastname: Sho
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nanjo
authors.forename: Tej M
authors.initials: TM
authors.lastname: Singh
authors.forename: Chengpei
authors.initials: C
authors.lastname: Xu
authors.forename: Hirotake
authors.initials: H
authors.lastname: Masuda
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Zarins
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001164:Arteriovenous Fistula / Q000503:physiopathology; D001783:Blood Flow Velocity / Q000502:physiology*; D015820:Cadherins / Q000096:biosynthesis; D002339:Carotid Arteries / Q000378:metabolism / Q000502:physiology; D002455:Cell Division; D004591:Electrophoresis, Polyacrylamide Gel; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008222:Lymphokines / Q000096:biosynthesis*; D008297:Male; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D011817:Rabbits; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D016228:Endothelial Growth Factors; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099152:Cadherin 5