title: Low-density lipoprotein receptor-related protein-1: role in the regulation of vascular integrity.
abstract: Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling receptor that is widely expressed. In the liver, LRP1 plays an important role in regulating the plasma levels of blood coagulation factor VIII (fVIII) by mediating its uptake and subsequent degradation. fVIII is a key plasma protein that is deficient in hemophilia A and circulates in complex with von Willebrand factor. Because von Willebrand factor blocks binding of fVIII to LRP1, questions remain on the molecular mechanisms by which LRP1 removes fVIII from the circulation. LRP1 also regulates cell surface levels of tissue factor, a component of the extrinsic blood coagulation pathway. This occurs when tissue factor pathway inhibitor bridges the fVII/tissue factor complex to LRP1, resulting in rapid LRP1-mediated internalization and downregulation of coagulant activity. In the vasculature LRP1 also plays protective role from the development of aneurysms. Mice in which the lrp1 gene is selectively deleted in vascular smooth muscle cells develop a phenotype similar to the progression of aneurysm formation in human patient, revealing that these mice are ideal for investigating molecular mechanisms associated with aneurysm formation. Studies suggest that LRP1 protects against elastin fiber fragmentation by reducing excess protease activity in the vessel wall. These proteases include high-temperature requirement factor A1, matrix metalloproteinase 2, matrix metalloproteinase-9, and membrane associated type 1-matrix metalloproteinase. In addition, LRP1 regulates matrix deposition, in part, by modulating levels of connective tissue growth factor. Defining pathways modulated by LRP1 that lead to aneurysm formation and defining its role in thrombosis may allow for more effective intervention in patients.
authors: From the Center for Vascular and Inflammatory Disease (D.K.S., D.T.A., P.C., S.C.M.), Departments of Surgery (D.K.S.), and Physiology (S.C.M.), University of Maryland School of Medicine, Baltimore.
authors: Dudley K
authors: DK
authors: Strickland
authors: Dianaly T
authors: DT
authors: Au
authors: Patricia
authors: P
authors: Cunfer
authors: Selen C
authors: SC
authors: Muratoglu
mesh_terms: D000783:Aneurysm / Q000517:prevention & control; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology; D004549:Elastin / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009928:Organ Specificity; D010447:Peptide Hydrolases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011487:Protein Conformation; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C475476:LRP1 protein, human; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010982:Platelet-Derived Growth Factor; D011973:Receptors, LDL; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D014841:von Willebrand Factor; D005169:Factor VIII; D004549:Elastin; D013925:Thromboplastin; D010447:Peptide Hydrolases
keywords: LRP1; aneurysm; elastin; extracellular matrix; fVIII