Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes.

Abstract

While testing the effect of the (β15-66)(2) fragment, which mimics a pair of fibrin βN-domains, on the morphology of endothelial cells, we found that this fragment induces redistribution of vascular endothelial-cadherin in a process that is inhibited by the receptor-associated protein (RAP). Based on this finding, we hypothesized that fibrin may interact with members of RAP-dependent low-density lipoprotein (LDL) receptor family. To test this hypothesis, we examined the interaction of (β15-66)(2), fibrin, and several fibrin-derived fragments with 2 members of this family by ELISA and surface plasmon resonance. The experiments showed that very LDL (VLDL) receptor (VLDLR) interacts with high affinity with fibrin through its βN-domains, and this interaction is inhibited by RAP and (β15-66)(2). Furthermore, RAP inhibited transendothelial migration of neutrophils induced by fibrin-derived NDSK-II fragment containing βN-domains, suggesting the involvement of VLDLR in fibrin-dependent leukocyte transmigration. Our experiments with VLDLR-deficient mice confirmed this suggestion by showing that, in contrast to wild-type mice, fibrin-dependent leukocyte transmigration does not occur in such mice. Altogether, the present study identified VLDLR as a novel endothelial cell receptor for fibrin that promotes fibrin-dependent leukocyte transmigration and thereby inflammation. Establishing the molecular mechanism underlying this interaction may result in the development of novel inhibitors of fibrin-dependent inflammation.

• Authors: Sergiy Yakovlev, Irina Mikhailenko, Chunzhang Cao, Li Zhang, Dudley K Strickland, Leonid Medved
• Journal: Blood (Blood) Vol. 119 Issue 2 Pg. 637-44 (Jan 12 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22096238 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, CD
• Cadherins
• Fibrin Fibrinogen Degradation Products
• LDL-Receptor Related Protein-Associated Protein
• NDSK-II
• Receptors, LDL
• VLDL receptor
• cadherin 5
• Fibrin

Topics

• Animals
• Antigens, CD (metabolism)
• Cadherins (metabolism)
• Cells, Cultured
• Endothelium, Vascular (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Fibrin (metabolism)
• Fibrin Fibrinogen Degradation Products (metabolism)
• Fluorescent Antibody Technique
• Humans
• LDL-Receptor Related Protein-Associated Protein (metabolism)
• Leukocytes (cytology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Peritonitis (etiology, metabolism, pathology)
• Receptors, LDL (physiology)
• Surface Plasmon Resonance
• Transendothelial and Transepithelial Migration (physiology)