P2y5/LPA 6 attenuates LPA 1-mediated VE-cadherin translocation and cellcell dissociation through G 12/13 proteinSrcRap1

Takao Kimura, Chihiro Mogi, Koichi Sato, Hideaki Tomura, Hideo Ohta, Doon Soon Im, Atsushi Kuwabara, Hitoshi Kurose, Masami Murakami, Fumikazu Okajima

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6 Citations (Scopus)

Abstract

Aims We investigated the mechanisms of action of lysophosphatidic acid (LPA) to regulate vascular endothelial (VE)-cadherin dynamics and cellcell contact. Methods and resultsWhile a low concentration of LPA stimulated VE-cadherin internalization and subsequent cellcell dissociation, a high concentration of LPA masked the disruptive actions on VE-cadherin and protected the barrier function in human vascular endothelial cells. Knockdown experiments of major LPA receptor subtypes, i.e. LPA1 and p2y5 (also termed LPA6), with their specific small interfering RNAs, showed that LPA1 and LPA6 mediate the LPA-induced disruptive and protective actions on barrier integrity, respectively. LPA6-mediated tube formation, reflecting stabilization of barrier integrity, was confirmed by in vitro angiogenesis assay. The LPA1-mediated disruptive actions were inhibited by pertussis toxin, dominant-negative Rac1, and inhibitors for c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), but not by dominant-negative RhoA. In contrast, the LPA6-mediated protective actions were associated with activation of Src and Rap1 and attenuated by abrogation of their activities. Further characterization showed that Rap1 is located downstream of Src and dependent on C3G, a Rap1 guanine nucleotide exchange factor. Finally, an LPA antagonist significantly inhibited lactic acid-induced limb lesions in vivo, which may be attributed to dysfunction of endothelial cells. ConclusionLPA induced disruption and protection of VE-cadherin integrity through LPA1Gi proteinRac1JNK/p38MAPK and LPA6G12/13 proteinSrcC3GRap1 pathways, respectively.

Original languageEnglish
Pages (from-to)149-158
Number of pages10
JournalCardiovascular research
Volume92
Issue number1
DOIs
Publication statusPublished - Oct 1 2011

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Kimura, T., Mogi, C., Sato, K., Tomura, H., Ohta, H., Im, D. S., Kuwabara, A., Kurose, H., Murakami, M., & Okajima, F. (2011). P2y5/LPA 6 attenuates LPA 1-mediated VE-cadherin translocation and cellcell dissociation through G 12/13 proteinSrcRap1. Cardiovascular research, 92(1), 149-158. https://doi.org/10.1093/cvr/cvr154