TY - JOUR
T1 - P2y5/LPA 6 attenuates LPA 1-mediated VE-cadherin translocation and cellcell dissociation through G 12/13 proteinSrcRap1
AU - Kimura, Takao
AU - Mogi, Chihiro
AU - Sato, Koichi
AU - Tomura, Hideaki
AU - Ohta, Hideo
AU - Im, Doon Soon
AU - Kuwabara, Atsushi
AU - Kurose, Hitoshi
AU - Murakami, Masami
AU - Okajima, Fumikazu
N1 - Funding Information:
This work was funded by grants from Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Takeda Science Foundation, and the National Research Foundation of Korea Grant (NRF-2010-616-E00015). This work was also supported in part by the joint research programme of the Institute for Molecular and Cellular Regulation, Gunma University (10004) and by 2010 Japan–Korean Joint Research Project Grant (E00015).
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
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U2 - 10.1093/cvr/cvr154
DO - 10.1093/cvr/cvr154
M3 - Article
C2 - 21632882
AN - SCOPUS:80052885398
VL - 92
SP - 149
EP - 158
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 1
ER -