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Cardiovascular Research Advance Access first published online on May 14, 2008
This version [Corrected Proof] published online on May 28, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn118
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

G12/13 and Gq mediate S1P2-induced inhibition of Rac and migration in vascular smooth muscle in a manner dependent on Rho but not Rho kinase

Shin-ichiro Takashima1,2, Naotoshi Sugimoto1, Noriko Takuwa1,3, Yasuo Okamoto1, Kazuaki Yoshioka1, Masayuki Takamura2, Shigeo Takata2, Shuichi Kaneko2 and Yoh Takuwa1,*

1 Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan
2 Department of Disease Control and Homeostasis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
3 Ishikawa Prefectural Nursing University, Kahoku, Japan

* Corresponding author. Tel: +81 76 265 2165; fax: +81 76 234 4223. E-mail address: ytakuwa{at}med.kanazawa-u.ac.jp

Aims: The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled receptors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, thereby, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs.

Methods and results: S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P2 receptor antagonist JTE-013. The C-terminal peptides of G{alpha} subunits (G{alpha}-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of G{alpha}12-CT, G{alpha}13-CT, and G{alpha}q-CT, but not that of G{alpha}s-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G12/13 and Gq classes are necessary for the S1P inhibition. The expression of G{alpha}q-CT as well as G{alpha}12-CT and G{alpha}13-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT1, which robustly couples to Gq, did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of Gq alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT1 receptor fused to G{alpha}12 was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway.

Conclusion: These observations together suggest that S1P2 mediates inhibition of Rac and migration through the coordinated action of G12/13 and Gq for Rho activation in VSMCs.

KEYWORDS Sphingosine-1-phosphate; Cell migration; Gq; G12/13; Rac; Rho; Vascular smooth muscle cell

Time for primary review: 22 days


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