Journal Article

Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point

Van den Dries, Koen, Mejean, Cecile O, Baeyens, Nicolas, Nicoli, Stefania, Coon, Brian G, Han, Jinah, Thomas, Jean-Leon, Humphrey, Jay D, Schwartz, Martin A, Lauridsen, Holly M, Eichmann, Anne, Ross, Tyler D

2015

Overview

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. Blood and lymphatic vessels remodel their shape, diameter and connections during development, and throughout life in response to growth, exercise and disease. This process is called vascular remodeling. The endothelial cells that line the inside of blood and lymphatic vessels are constantly exposed to the frictional force from flowing blood, termed fluid shear stress. Changes in shear stress are sensed by the endothelial cells, which trigger vascular remodeling to return the stress to the original level. It has been proposed that remodeling is governed by a preferred level of fluid shear stress, or set point, against which deviations in the shear stress are compared. Thus, changing the fluid flow through a blood vessel increases or decreases shear stress, which results in the vessel remodeling to restore the original level of shear stress. Like all remodeling, this process involves inflammation to recruit white blood cells, which assist with the process. Baeyens et al. investigated whether such a shear stress set point exists and what its biological basis might be using cultured endothelial cells from human umbilical veins. These cells remained stable and in a resting state when a particular level of shear stress was applied to them; above or below this shear stress level, the cells produced an inflammatory response like that seen during vascular remodeling. This suggests that these cells do indeed have a set point for shear stress. The same response occurred in human lymphatic endothelial cells, although in these cells the shear stress set point was much lower, correlating with the low flow in lymphatic vessels. Baeyens et al. then discovered that the shear stress set point is related to the level of a protein called VEGFR3 in the cells, which was recently found to participate in shear stress sensing. Endothelial cells from lymphatic vessels normally produce much greater quantities of VEGFR3 than those from blood vessels. Reducing the amount of VEGFR3 in lymphatic endothelial cells increased the set point shear stress, while increasing the levels in blood vessel cells decreased the set point. This suggests that the levels of this protein account for the difference in the response of these two cell types. Baeyens et al. then tested this pathway by reducing the levels of VEGFR3 in zebrafish embryos and in adult mice. In both animals, this caused arteries to narrow, showing that VEGFR3 levels also control sensitivity to shear stress—and hence vascular remodeling—inside living creatures. Understanding in detail how vascular remodeling is regulated could help improve treatments for a wide range of cardiovascular conditions. To do so, further work will be needed to develop methods to control the sensitivity of endothelial cells to shear stress and to identify other proteins that might specifically control the narrowing or the expansion of vessels in human patients.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: Animals / Aorta / arteriogenesis / Cell Biology / Cellular Biology / Coronary vessels / Endothelial cells / Endothelium / Endothelium, Vascular - physiology / Fluid flow / homeostasis / Human Biology and Medicine / Human Umbilical Vein Endothelial Cells / Humans / Hypotheses / Life Sciences / Mechanical stimuli / mechanotransduction / Medical research / Medicine / Mice / Physiology / Shear stress / Skin / Stress, Physiological / Umbilical vein / Umbilical Veins - physiology / Variance analysis / Vascular Endothelial Growth Factor Receptor-3 - physiology / Vascular endothelial growth factor receptors / Vascular Remodeling / Zebrafish