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Development. 2016 Dec 1;143(23):4441-4451. Epub 2016 Oct 27.

Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development.

Author information

1
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
2
Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT 06520, USA.
5
Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA michael.simons@yale.edu.

Abstract

The role of fluid shear stress in vasculature development and remodeling is well appreciated. However, the mechanisms regulating these effects remain elusive. We show that abnormal flow sensing in lymphatic endothelial cells (LECs) caused by Sdc4 or Pecam1 deletion in mice results in impaired lymphatic vessel remodeling, including abnormal valve morphogenesis. Ablation of either gene leads to the formation of irregular, enlarged and excessively branched lymphatic vessels. In both cases, lymphatic valve-forming endothelial cells are randomly oriented, resulting in the formation of abnormal valves. These abnormalities are much more pronounced in Sdc4-/-; Pecam1-/- double-knockout mice, which develop severe edema. In vitro, SDC4 knockdown human LECs fail to align under flow and exhibit high expression of the planar cell polarity protein VANGL2. Reducing VANGL2 levels in SDC4 knockdown LECs restores their alignment under flow, while VANGL2 overexpression in wild-type LECs mimics the flow alignment abnormalities seen in SDC4 knockdown LECs. SDC4 thus controls flow-induced LEC polarization via regulation of VANGL2 expression.

KEYWORDS:

Embryonic development; Lymphatic remodeling; Syndecan 4

PMID:
27789626
PMCID:
PMC5201046
[Available on 2017-12-01]
DOI:
10.1242/dev.140129
[Indexed for MEDLINE]
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