The interaction between factor H and VWF increases factor H cofactor activity and regulates VWF prothrombotic status

Area of Science:

• Biochemistry
• Cell Biology
• Immunology

Background:

• Vascular endothelial cells (ECs) play a crucial role in hemostasis, thrombosis, and complement regulation.
• ECs synthesize both von Willebrand factor (VWF), a key clotting initiator, and factor H (FH), a complement regulator.
• The intracellular localization and interaction of VWF and FH within ECs were not well-defined.

Purpose of the Study:

• To investigate the intracellular localization and interaction of factor H (FH) and von Willebrand factor (VWF) within endothelial cells (ECs).
• To elucidate the functional consequences of the VWF-FH interaction on complement activation and hemostasis.
• To describe a novel link between the complement and hemostasis systems mediated by ECs.

Main Methods:

• Immunofluorescence microscopy to determine the colocalization of FH and VWF in human umbilical vein ECs.
• Biochemical assays to assess the binding affinity between VWF and FH.
• Functional assays to evaluate the impact of the VWF-FH complex on complement regulation (FH cofactor activity) and VWF proteolysis (ADAMTS13 activity).
• Assessment of platelet aggregation in response to the VWF-FH interaction.

Main Results:

• Factor H (FH) was found to colocalize with von Willebrand factor (VWF) in Weibel-Palade bodies (WPBs) of endothelial cells.
• FH demonstrated high-affinity binding to VWF, forming a complex detectable in normal plasma.
• The VWF-FH interaction enhanced FH's cofactor activity for complement downregulation.
• This interaction also inhibited ADAMTS13-mediated VWF cleavage and promoted platelet aggregation.

Conclusions:

• A novel interaction between the complement and hemostasis systems has been identified, involving the colocalization and binding of FH and VWF within ECs.
• The simultaneous secretion of VWF and FH by activated ECs can promote platelet adhesion at sites of endothelial injury, aiding wound healing.
• This interaction simultaneously modulates complement activation, potentially limiting bystander tissue damage during inflammatory responses.