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

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, LPA, LPA, and LPA In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA antagonist Ki16425, and genetic deletion of LPA but not that of LPA or inhibition of LPA, by diacylglycerol pyrophosphate. 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 (TXA) release from TA of wild-type, TP-KO, and LPA-KO mice but not from LPA-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA-, G-, and COX1-dependent autocrine/paracrine TXA release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA and TXA/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 receptor-mediated thromboxane A release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction.

Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure

“…Thoracic aortae were cut into segments and were placed on stainless steel vessel holders (200 μm in diameter) in a myograph (610M multiwire myograph system, Danish Myo Technology A/S). Experimental protocol was described previously (17,71). Mice used for the experiments were caged with blinded identity and in random order.…”

Novel role for lysophosphatidic acid in vascular remodeling at the maternal–fetal interface

“…Studies performed in mice and human revealed that smooth muscle cells (Panchatcharam et al 2008, Subramanian et al 2010, Dancs et al 2017, endothelial cells (Zhou et al 2011) and platelets (Haserück et al 2004, Pamuklar et al 2008 present in the vasculature respond to LPA (Cheng et al 2009, Morris et al 2009a. These interactions are involved in the regulation of blood vessel development and contribute to vascular biology and pathology (Mueller et al 2015).…”

Lysophosphatidic acid acts on LPA1receptor to increase H2O2during flow‐induced dilation in human adipose arterioles

“…Lack of pronounced expression of LPA receptors, in particular LPA 1 receptor, in arteriolar tunica intima was an unexpected finding. Prior findings in animal models and endothelial cell cultures show majority of LPA effects being mediated through LPA 1 receptor (Gobeil et al ., ; Brault et al ., ; Cui, ; Ruisanchez et al ., ; Dancs et al ., ). Additionally, we and others observe strong protein and RNA expression in cultured endothelial cells (Lin et al ., ; Ptaszynska et al ., ; Ren et al ., ).…”

“…Faint expression of LPA 3 receptor protein was also detected in HUVECs. Absence or minimal expression of LPA 3 has been observed in endothelial (Lee et al ., ; Lin et al ., ; Ruisanchez et al ., ) and smooth muscle (Dancs et al ., ) cells from animal models or cultured vascular human cell lines. We confirmed previously published data using HUVEC and HMVECs.…”