6533b7ddfe1ef96bd1275506
RESEARCH PRODUCT
The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development
Kai ZurhoveHans H. BockJoachim HerzMichael FrotscherSebastian M. GoerkeChikako NakajimaPetra MayPetra MayPhilipp HaffnerGiselind Adelmannsubject
AngiogenesisBlotting WesternBecaplerminEmbryonic DevelopmentNeovascularization PhysiologicRAC1BiologyReal-Time Polymerase Chain ReactionMural cellchemistry.chemical_compoundMiceCell MovementSphingosineHuman Umbilical Vein Endothelial CellsAnimalsHumansSphingosine-1-phosphateMolecular BiologyResearch ArticlesIn Situ HybridizationSphingosineTumor Suppressor ProteinsCell migrationCell BiologyProto-Oncogene Proteins c-sisLRP1ImmunohistochemistryCell biologyMicroscopy ElectronchemistryReceptors LDLLow-density lipoproteinSignal transductionLysophospholipidsGenetic EngineeringLow Density Lipoprotein Receptor-Related Protein-1Developmental BiologySignal Transductiondescription
Low density lipoprotein receptor-related protein 1 (LRP1) is indispensable for embryonic development. Comparing different genetically engineered mouse models, we found that expression of Lrp1 is essential in the embryo proper. Loss of LRP1 leads to lethal vascular defects with lack of proper investment with mural cells of both large and small vessels. We further demonstrate that LRP1 modulates Gi-dependent sphingosine-1-phosphate (S1P) signaling and integrates S1P and PDGF-BB signaling pathways, which are both crucial for mural cell recruitment, via its intracellular domain. Loss of LRP1 leads to a lack of S1P-dependent inhibition of RAC1 and loss of constraint of PDGF-BB-induced cell migration. Our studies thus identify LRP1 as a novel player in angiogenesis and in the recruitment and maintenance of mural cells. Moreover, they reveal an unexpected link between lipoprotein receptor and sphingolipid signaling that, in addition to angiogenesis during embryonic development, is of potential importance for other targets of these pathways, such as tumor angiogenesis and inflammatory processes.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2014-12-01 |