| First Author | Rastegarlari G | Year | 2012 |
| Journal | Blood | Volume | 119 |
| Issue | 9 | Pages | 2126-34 |
| PubMed ID | 22234691 | Mgi Jnum | J:182558 |
| Mgi Id | MGI:5315834 | Doi | 10.1182/blood-2011-08-373605 |
| Citation | Rastegarlari G, et al. (2012) Macrophage LRP1 contributes to the clearance of von Willebrand factor. Blood 119(9):2126-34 |
| abstractText | 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 beta2-integrins that binds both VWF and LRP1 also is implicated because inhibition of beta2-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). |
