LPA₁ receptor-mediated thromboxane A₂ release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction

Lysophosphatidic acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA₁, LPA₂, LPA₄, and LPA₆. In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and theLPA_1-3 agonistVPC31143 induced dosedependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA_1&3 antagonist Ki16425, and genetic deletion of LPA₁ but not that of LPA₂ or inhibition of LPA₃, by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxaneprostanoid (TP) receptor (TPKO).VPC31143 increased thromboxaneA₂(TXA₂) release from TA of wild-type, TP-KO, and LPA₂-KO mice but not from LPA₁-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA₁-, G_i-, and COX₁-dependent autocrine/paracrine TXA₂ release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA1 and TXA2/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.