The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development
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The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development. / Nakajima, Chikako; Haffner, Philipp; Goerke, Sebastian M; Zurhove, Kai; Adelmann, Giselind; Frotscher, Michael; Herz, Joachim; Bock, Hans H; May, Petra.
In: DEVELOPMENT, Vol. 141, No. 23, 01.12.2014, p. 4513-25.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development
AU - Nakajima, Chikako
AU - Haffner, Philipp
AU - Goerke, Sebastian M
AU - Zurhove, Kai
AU - Adelmann, Giselind
AU - Frotscher, Michael
AU - Herz, Joachim
AU - Bock, Hans H
AU - May, Petra
N1 - © 2014. Published by The Company of Biologists Ltd.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
KW - Animals
KW - Blotting, Western
KW - Cell Movement
KW - Embryonic Development
KW - Genetic Engineering
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Immunohistochemistry
KW - In Situ Hybridization
KW - Lysophospholipids
KW - Mice
KW - Microscopy, Electron
KW - Neovascularization, Physiologic
KW - Proto-Oncogene Proteins c-sis
KW - Real-Time Polymerase Chain Reaction
KW - Receptors, LDL
KW - Signal Transduction
KW - Sphingosine
KW - Tumor Suppressor Proteins
U2 - 10.1242/dev.109124
DO - 10.1242/dev.109124
M3 - SCORING: Journal article
C2 - 25377550
VL - 141
SP - 4513
EP - 4525
JO - DEVELOPMENT
JF - DEVELOPMENT
SN - 0950-1991
IS - 23
ER -
