title: LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1.
abstract: OBJECTIVE
  Low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is abundant in vascular smooth muscle cells. Mice in which the lrp1 gene is deleted in smooth muscle cells (smLRP1(-/-)) on a low-density lipoprotein receptor-deficient background display excessive platelet derived growth factor-signaling, smooth muscle cell proliferation, aneurysm formation, and increased susceptibility to atherosclerosis. The objectives of the current study were to examine the potential of LRP1 to modulate vascular physiology under nonatherogenic conditions.
  
  
  RESULTS
  We found smLRP1(-/-) mice to have extensive in vivo aortic dilatation accompanied by disorganized and degraded elastic lamina along with medial thickening of the arterial vessels resulting from excess matrix deposition. Surprisingly, this was not attributable to excessive platelet derived growth factor-signaling. Rather, quantitative differential proteomic analysis revealed that smLRP1(-/-) vessels contain a 4-fold increase in protein levels of high-temperature requirement factor A1 (HtrA1), which is a secreted serine protease that is known to degrade matrix components and to impair elastogenesis, resulting in fragmentation of elastic fibers. Importantly, our study discovered that HtrA1 is a novel LRP1 ligand. Proteomics analysis also identified excessive accumulation of connective tissue growth factor, an LRP1 ligand and a key mediator of fibrosis.
  
  
  CONCLUSIONS
  Our findings suggest a critical role for LRP1 in maintaining the integrity of vessels by regulating protease activity as well as matrix deposition by modulating HtrA1 and connective tissue growth factor protein levels. This study highlights 2 new molecules, connective tissue growth factor and HtrA1, which contribute to detrimental changes in the vasculature and, therefore, represent new target molecules for potential therapeutic intervention to maintain vessel wall homeostasis.
authors.affiliation: Center for Vascular and Inflammatory Disease, Departments of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Selen C
authors.initials: SC
authors.lastname: Muratoglu
authors.forename: Shani
authors.initials: S
authors.lastname: Belgrave
authors.forename: Brian
authors.initials: B
authors.lastname: Hampton
authors.forename: Mary
authors.initials: M
authors.lastname: Migliorini
authors.forename: Turhan
authors.initials: T
authors.lastname: Coksaygan
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Irina
authors.initials: I
authors.lastname: Mikhailenko
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000503:physiopathology / Q000648:ultrastructure; D001025:Aortitis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004108:Dilatation, Pathologic; D004547:Elastic Tissue / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D000074289:High-Temperature Requirement A Serine Peptidase 1; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D040901:Proteomics / Q000379:methods; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C526318:CCN2 protein, mouse; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases
keywords: Ctgf protein, mouse; HtrA1 protein, mouse; Lrp1 protein, mouse; collagen; lamina elastica