Work

LPA 1 receptor–mediated thromboxane A 2 release is responsible for lysophosphatidic acid‐induced vascular smooth muscle contraction

Year: 2017

Type: article

Abstract: 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 LPA 1 , LPA 2 , LPA 4 , and LPA 6 . In endothelium‐denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1‐oleoyl‐LPA and the LPA 1–3 agonist VPC31143 induced dose‐dependent vasoconstriction. VPC31143‐induced AA contraction was sensitive to pertussis toxin (PTX), the LPA 1&3 antagonist Ki16425, and genetic deletion of LPA 1 but not that of LPA 2 or inhibition of LPA 3 , by diacylglycerol pyro‐phosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase‐1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A 2 (TXA 2 ) release from TA of wild‐type, TP‐KO, and LPA 2 ‐KO mice but not from LPA 1 ‐KO or COX1‐KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA 1 ‐, G i ‐, and COX1‐dependent autocrine/paracrine TXA 2 release and consequent TP activation. We propose that this new‐found interaction between the LPA/LPA 1 and TXA 2 /TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling. —Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklós, Z., Nüsing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyó, Z. LPA 1 receptor‐mediated thromboxane A 2 release is responsible for lysophos‐phatidic acid‐induced vascular smooth muscle contraction. FASEB J . 31, 1547–1555 (2017) www.fasebj.org

Source: The FASEB Journal

DOI: 10.1096/fj.201600735r