title: Macrophage LRP1 contributes to the clearance of von Willebrand factor.
abstract: The relationship between low-density lipoprotein receptor-related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophage-specific deficiency of LRP1 (macLRP1(-)) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1(-) mice compared with control mice (1.6 ± 0.4 vs 1.0 ± 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1(-) mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1(-) mice did not result in further rise of VWF levels (0.1 ± 0.2 U/mL), in contrast to macLRP1(+) mice (rise in VWF, 0.8 ± 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWF-coated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm(2), implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving β2-integrins that binds both VWF and LRP1 also is implicated because inhibition of β2-integrins led to increased VWF levels in control (rise, 0.19 ± 0.16 U/mL) but not in macLRP1(-) mice (0.08 ± 0.15 U/mL).
authors.affiliation: INSERM U770, Université Paris Sud, 80 rue du Général Leclerc, Le Kremlin-Bicêtre, France.
authors.forename: Ghasem
authors.initials: G
authors.lastname: Rastegarlari
authors.forename: Julie N
authors.initials: JN
authors.lastname: Pegon
authors.forename: Caterina
authors.initials: C
authors.lastname: Casari
authors.forename: Soline
authors.initials: S
authors.lastname: Odouard
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Navarrete
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saint-Lu
authors.forename: Bart J
authors.initials: BJ
authors.lastname: van Vlijmen
authors.forename: Paulette
authors.initials: P
authors.lastname: Legendre
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Christophe
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
mesh_terms: D000818:Animals; D005169:Factor VIII / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D011973:Receptors, LDL / Q000037:antagonists & inhibitors; D033081:Shear Strength; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D039641:Integrin beta Chains; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011973:Receptors, LDL; D014841:von Willebrand Factor; D005169:Factor VIII