Syndecan-4 controls lymphatic vasculature remodeling during embryonic development

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 Pecam-1 deletion in mice results in impaired lymphatic vessel remodeling including abnormal valve morphogenesis. Ablation of either gene leads to formation of irregular, enlarged, and excessively branched lymphatic vessels. In both cases, lymphatic-valve-forming endothelial cells are randomly oriented, resulting in formation of abnormal valves. These abnormalities are much more pronounced in Sdc4(-/-);Pecam-1(-/-) double knockout mice that develop severe edema. In vitro, SDC4-knockdown 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 its overexpression in wildtype LECs mimics flow-alignment abnormalities seen in SDC4-knockdown LECs. Syndecan-4 thus controls flow-induced LEC polarization via regulation of VANGL2 expression.