title: 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.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, 21201, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Yakovlev
authors.forename: Irina
authors.initials: I
authors.lastname: Mikhailenko
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Cao
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.forename: Leonid
authors.initials: L
authors.lastname: Medved
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005337:Fibrin / Q000378:metabolism*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000502:physiology*; D020349:Surface Plasmon Resonance; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D005337:Fibrin; D005338:Fibrin Fibrinogen Degradation Products; D026563:LDL-Receptor Related Protein-Associated Protein; D011973:Receptors, LDL; D000099152:Cadherin 5; C500232:NDSK-II; C036053:VLDL receptor
references.citation: Blood. 2005 May 1;105(9):3561-8
references.pmid: 15637140
references.citation: Cell. 1989 Sep 8;58(5):945-53
references.pmid: 2673537
references.citation: Thromb Haemost. 2004 Jun;91(6):1056-64
references.pmid: 15175790
references.citation: Thromb Haemost. 1999 Aug;82(2):781-6
references.pmid: 10605782
references.citation: Biochemistry. 2000 Dec 26;39(51):15730-41
references.pmid: 11123898
references.citation: Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):652-8
references.pmid: 10712387
references.citation: PLoS One. 2009;4(4):e5391
references.pmid: 19401765
references.citation: J Biol Chem. 1992 May 5;267(13):9035-40
references.pmid: 1374383
references.citation: Cell. 1993 Jul 2;73(7):1423-34
references.pmid: 8100742
references.citation: Nat Med. 2005 Mar;11(3):298-304
references.pmid: 15723073
references.citation: J Thromb Haemost. 2006 Sep;4(9):1975-81
references.pmid: 16961604
references.citation: Biochemistry. 2003 Jul 1;42(25):7709-16
references.pmid: 12820880
references.citation: J Cell Biol. 1990 Apr;110(4):1041-8
references.pmid: 1691187
references.citation: J Biol Chem. 1991 Jul 15;266(20):13364-9
references.pmid: 1712782
references.citation: Int J Cancer. 2009 Aug 1;125(3):577-84
references.pmid: 19358279
references.citation: Biochemistry. 2009 Jun 16;48(23):5171-9
references.pmid: 19413351
references.citation: Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1544-51
references.pmid: 8977460
references.citation: J Biol Chem. 1998 Nov 13;273(46):30719-28
references.pmid: 9804847
references.citation: Blood. 1991 Apr 1;77(7):1469-75
references.pmid: 1706954
references.citation: Biochemistry. 2002 Mar 26;41(12):4107-16
references.pmid: 11900554
references.citation: Ann N Y Acad Sci. 2001;936:386-405
references.pmid: 11460494
references.citation: J Lipid Res. 2005 Aug;46(8):1721-31
references.pmid: 15863833
references.citation: Int J Biochem Cell Biol. 2002 Jul;34(7):838-54
references.pmid: 11950599
references.citation: J Cell Biol. 1995 Jul;130(1):207-15
references.pmid: 7540617
references.citation: J Biol Chem. 1991 Nov 5;266(31):21232-8
references.pmid: 1718973
references.citation: J Biol Chem. 1997 Feb 21;272(8):5360-6
references.pmid: 9030612
references.citation: Mol Med. 2011 May-Jun;17(5-6):568-73
references.pmid: 21210072
references.citation: J Thromb Haemost. 2011 Sep;9(9):1847-55
references.pmid: 21752185
references.citation: Biochemistry. 2002 May 21;41(20):6449-59
references.pmid: 12009908
references.citation: J Mol Med (Berl). 2006 Jun;84(6):469-77
references.pmid: 16733765