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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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VEGFR3 and DAPI staining of a longitudinal section different portions of the aorta. Scale bar: 50 µm.DOI:http://dx.doi.org/10.7554/eLife.04645.015
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fig7s1: VEGFR3 and DAPI staining of a longitudinal section different portions of the aorta. Scale bar: 50 µm.DOI:http://dx.doi.org/10.7554/eLife.04645.015

Mentions: Lastly, we investigated whether VEGFR3 controls artery remodeling in mice in a similar manner. Expression of VEGFR3 in adult arteries has been reported to be low (Gu et al., 2001; Witmer et al., 2002; Tammela et al., 2008), thus, we first verified its transcription in the thoracic aorta. Using a transgenic Vegfr3::YFP reporter mouse (Calvo et al., 2011), expression of YFP was readily detected, confirming Vegfr3 expression in adult arteries (Figure 7A). We confirmed this observation by staining a longitudinal section of the thoracic aorta with an anti-VEGFR-3 antibody (Figure 7B). Interestingly, VEGFR3 expression was not uniform: weaker expression was detected in the outer curvature or some portions of the carotid artery, associated with higher shear stress, while stronger expression was observed in the inner curvature, associated with low shear stress (Figure 7—figure supplement 1).10.7554/eLife.04645.014Figure 7.Transient vascular remodeling in EC iΔR3 mice.


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)

VEGFR3 and DAPI staining of a longitudinal section different portions of the aorta. Scale bar: 50 µm.DOI:http://dx.doi.org/10.7554/eLife.04645.015
© Copyright Policy
Related In: Results  -  Collection

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

fig7s1: VEGFR3 and DAPI staining of a longitudinal section different portions of the aorta. Scale bar: 50 µm.DOI:http://dx.doi.org/10.7554/eLife.04645.015
Mentions: Lastly, we investigated whether VEGFR3 controls artery remodeling in mice in a similar manner. Expression of VEGFR3 in adult arteries has been reported to be low (Gu et al., 2001; Witmer et al., 2002; Tammela et al., 2008), thus, we first verified its transcription in the thoracic aorta. Using a transgenic Vegfr3::YFP reporter mouse (Calvo et al., 2011), expression of YFP was readily detected, confirming Vegfr3 expression in adult arteries (Figure 7A). We confirmed this observation by staining a longitudinal section of the thoracic aorta with an anti-VEGFR-3 antibody (Figure 7B). Interestingly, VEGFR3 expression was not uniform: weaker expression was detected in the outer curvature or some portions of the carotid artery, associated with higher shear stress, while stronger expression was observed in the inner curvature, associated with low shear stress (Figure 7—figure supplement 1).10.7554/eLife.04645.014Figure 7.Transient vascular remodeling in EC iΔR3 mice.

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