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

Baeyens N, Nicoli S, Coon BG, Ross TD, Van den Dries K, Han J, Lauridsen HM, Mejean CO, Eichmann A, Thomas JL, Humphrey JD, Schwartz MA - Elife (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.

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.

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Testing the set point hypothesis.(A) Definition of the ‘shear stress set point’. (B) Picture of a silicone gasket used in the gradient flow chamber with the corresponding calculation of the theoretical shear stress level across the channel with two different conditions of gasket thickness and flow rate.DOI:http://dx.doi.org/10.7554/eLife.04645.003
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fig1: Testing the set point hypothesis.(A) Definition of the ‘shear stress set point’. (B) Picture of a silicone gasket used in the gradient flow chamber with the corresponding calculation of the theoretical shear stress level across the channel with two different conditions of gasket thickness and flow rate.DOI:http://dx.doi.org/10.7554/eLife.04645.003

Mentions: Homeostasis, one of the central concepts in physiology (Cannon, 1929), posits that physiological variables have an optimum value or set point such that deviations from that set point activate responses that return those variables toward their original value. For example, changes in central body temperature trigger sweating, altered blood flow to the skin or shivering to restore normal temperature. In the vasculature, arteries remodel under sustained changes in blood flow, with increased or decreased flow triggering outward or inward remodeling, respectively, to adjust lumen diameters accordingly (Thoma, 1893; Kamiya and Togawa, 1980; Kamiya et al., 1984; Langille and O'Donnell, 1986; Langille et al., 1989; Langille, 1996; Tronc et al., 1996; Tuttle et al., 2001). These studies have given rise to the concept that the endothelium encodes a fluid shear stress set point that governs remodeling responses (Rodbard, 1975; Cardamone and Humphrey, 2012) (Figure 1A). While appealing, there is no direct evidence for such a mechanism. Moreover, if it exists, the set point must itself be variable, since different types of vessels, for example, arteries, veins and lymphatics, generally have very different magnitudes of fluid shear stress (Lipowsky et al., 1980; Dixon et al., 2006; Suo et al., 2007).10.7554/eLife.04645.003Figure 1.Testing the set point hypothesis.


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

Baeyens N, Nicoli S, Coon BG, Ross TD, Van den Dries K, Han J, Lauridsen HM, Mejean CO, Eichmann A, Thomas JL, Humphrey JD, Schwartz MA - Elife (2015)

Testing the set point hypothesis.(A) Definition of the ‘shear stress set point’. (B) Picture of a silicone gasket used in the gradient flow chamber with the corresponding calculation of the theoretical shear stress level across the channel with two different conditions of gasket thickness and flow rate.DOI:http://dx.doi.org/10.7554/eLife.04645.003
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4337723&req=5

fig1: Testing the set point hypothesis.(A) Definition of the ‘shear stress set point’. (B) Picture of a silicone gasket used in the gradient flow chamber with the corresponding calculation of the theoretical shear stress level across the channel with two different conditions of gasket thickness and flow rate.DOI:http://dx.doi.org/10.7554/eLife.04645.003
Mentions: Homeostasis, one of the central concepts in physiology (Cannon, 1929), posits that physiological variables have an optimum value or set point such that deviations from that set point activate responses that return those variables toward their original value. For example, changes in central body temperature trigger sweating, altered blood flow to the skin or shivering to restore normal temperature. In the vasculature, arteries remodel under sustained changes in blood flow, with increased or decreased flow triggering outward or inward remodeling, respectively, to adjust lumen diameters accordingly (Thoma, 1893; Kamiya and Togawa, 1980; Kamiya et al., 1984; Langille and O'Donnell, 1986; Langille et al., 1989; Langille, 1996; Tronc et al., 1996; Tuttle et al., 2001). These studies have given rise to the concept that the endothelium encodes a fluid shear stress set point that governs remodeling responses (Rodbard, 1975; Cardamone and Humphrey, 2012) (Figure 1A). While appealing, there is no direct evidence for such a mechanism. Moreover, if it exists, the set point must itself be variable, since different types of vessels, for example, arteries, veins and lymphatics, generally have very different magnitudes of fluid shear stress (Lipowsky et al., 1980; Dixon et al., 2006; Suo et al., 2007).10.7554/eLife.04645.003Figure 1.Testing the set point hypothesis.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, United States.

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.

Show MeSH
Related in: MedlinePlus