title: Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point.
abstract: Vascular remodeling under conditions of growth or exercise, or during recovery from arterial restriction or blockage is essential for health, but mechanisms are poorly understood. It has been proposed that endothelial cells have a preferred level of fluid shear stress, or 'set point', that determines remodeling. We show that human umbilical vein endothelial cells respond optimally within a range of fluid shear stress that approximate physiological shear. Lymphatic endothelial cells, which experience much lower flow in vivo, show similar effects but at lower value of shear stress. VEGFR3 levels, a component of a junctional mechanosensory complex, mediate these differences. Experiments in mice and zebrafish demonstrate that changing levels of VEGFR3/Flt4 modulates aortic lumen diameter consistent with flow-dependent remodeling. These data provide direct evidence for a fluid shear stress set point, identify a mechanism for varying the set point, and demonstrate its relevance to vessel remodeling in vivo.
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Nicolas
authors: N
authors: Baeyens
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Stefania
authors: S
authors: Nicoli
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Brian G
authors: BG
authors: Coon
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Tyler D
authors: TD
authors: Ross
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Koen
authors: K
authors: Van den Dries
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Jinah
authors: J
authors: Han
authors: Department of Biomedical Engineering, Yale University School of Engineering and Applied Science, New Haven, United States.
authors: Holly M
authors: HM
authors: Lauridsen
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Cecile O
authors: CO
authors: Mejean
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Anne
authors: A
authors: Eichmann
authors: Department of Neurology, Yale University School of Medicine, New Haven, United States.
authors: Jean-Leon
authors: JL
authors: Thomas
authors: Department of Biomedical Engineering, Yale University School of Engineering and Applied Science, New Haven, United States.
authors: Jay D
authors: JD
authors: Humphrey
authors: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.
authors: Martin A
authors: MA
authors: Schwartz
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D013312:Stress, Physiological; D014471:Umbilical Veins / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology*; D066253:Vascular Remodeling; D015027:Zebrafish
chemical_list: C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: arteriogenesis; cell biology; homeostasis; human; human biology; mechanotransduction; medicine; mouse; shear stress; vascular remodeling; zebrafish
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