The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development.
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.
Department of Medicine II, University Hospital and University of Freiburg, 79106 Freiburg, Germany Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany Institute of Physiological Chemistry and Focus Program Translational Neuroscience (Adult Neurogenesis and Cellular Reprogramming), University Medical Center, Johannes Gutenberg University Mainz, 55128 Mainz, Germany Department of Gastroenterology, Hepatology and Infectiology, University Hospital of Düsseldorf, 40225 Düsseldorf, Germany.
Chikako
C
Nakajima
Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany.
Philipp
P
Haffner
Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany Department of Plastic and Hand Surgery, University Hospital and University of Freiburg, 79106 Freiburg, Germany.
Sebastian M
SM
Goerke
Department of Medicine II, University Hospital and University of Freiburg, 79106 Freiburg, Germany Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany.
Kai
K
Zurhove
Institute of Anatomy and Cell Biology, University Hospital and University of Freiburg, 79104 Freiburg, Germany.
Giselind
G
Adelmann
Institute for Structural Neurobiology, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Michael
M
Frotscher
Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany Department for Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Joachim
J
Herz
Department of Medicine II, University Hospital and University of Freiburg, 79106 Freiburg, Germany Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany Department of Gastroenterology, Hepatology and Infectiology, University Hospital of Düsseldorf, 40225 Düsseldorf, Germany.
Hans H
HH
Bock
Department of Medicine II, University Hospital and University of Freiburg, 79106 Freiburg, Germany Centre for Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany Department of Gastroenterology, Hepatology and Infectiology, University Hospital of Düsseldorf, 40225 Düsseldorf, Germany petra.may@med.uni-duesseldorf.de.
Petra
P
May
D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology*; D005818:Genetic Engineering; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D008246:Lysophospholipids; D020574:Proto-Oncogene Proteins c-sis; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D000077214:Becaplermin; C060506:sphingosine 1-phosphate; D013110:Sphingosine
Angiogenesis; Lipoprotein receptor; Sphingolipid