The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development

Chikako Nakajima, Philipp Haffner, Sebastian M. Goerke, Kai Zurhove, Giselind Adelmann, Michael Frotscher, Joachim Herz, Hans H. Bock, Petra May

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4513-4525
Number of pages13
JournalDevelopment (Cambridge)
Volume141
Issue number23
DOIs
StatePublished - Dec 1 2014

Keywords

  • Angiogenesis
  • Lipoprotein receptor
  • Sphingolipid

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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    Nakajima, C., Haffner, P., Goerke, S. M., Zurhove, K., Adelmann, G., Frotscher, M., Herz, J., Bock, H. H., & May, P. (2014). The lipoprotein receptor LRP1 modulates sphingosine-1-phosphate signaling and is essential for vascular development. Development (Cambridge), 141(23), 4513-4525. https://doi.org/10.1242/dev.109124