Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development

Area of Science:

• Vascular Biology
• Cell Biology
• Developmental Biology

Background:

• Fluid shear stress is a critical factor in blood and lymphatic vasculature development and remodeling.
• The precise molecular mechanisms by which endothelial cells sense and respond to shear stress, particularly in lymphatic vessels, are not fully understood.

Purpose of the Study:

• To investigate the role of Syndecan-4 (Sdc4) and Platelet Endothelial Cell Adhesion Molecule-1 (Pecan1) in regulating lymphatic endothelial cell (LEC) responses to fluid shear stress.
• To elucidate the molecular pathways involved in flow-induced LEC polarization and lymphatic vessel remodeling.

Main Methods:

• Utilized knockout mouse models (Sdc4-/-, Pecam1-/-, and double knockouts) to study lymphatic vessel development and valve morphogenesis.
• Employed in vitro studies involving SDC4 knockdown in human LECs and manipulation of VANGL2 expression to assess cell alignment under flow conditions.

Main Results:

• Deletion of Sdc4 or Pecam1 in mice resulted in impaired lymphatic vessel remodeling, characterized by irregular, enlarged, and excessively branched vessels with abnormal valve formation.
• Simultaneously deleting both Sdc4 and Pecam1 led to severe lymphedema.
• In vitro, SDC4 knockdown in LECs abolished flow-induced alignment and increased VANGL2 expression. Reducing VANGL2 rescued alignment, while its overexpression mimicked SDC4 knockdown phenotypes.

Conclusions:

• Sdc4 and Pecam1 play crucial roles in mechanosensing and regulating lymphatic endothelial cell behavior under fluid flow.
• SDC4-mediated regulation of VANGL2 is essential for proper flow-induced LEC polarization and lymphatic vessel development.
• These findings reveal novel molecular mechanisms governing shear stress responses in lymphatic vasculature.