Lysophosphatidic acid induces vasodilation mediated by LPA ₁ receptors, phospholipase C, and endothelial nitric oxide synthase

Abstract

Lysophosphatidic acid (LPA) has been implicated as a mediator of several cardiovascular functions, but its potential involvement in the control of vascular tone is obscure. Here, we show that both LPA (18:1) and VPC31143 (a synthetic agonist of LPA1-3 receptors) relax intact mouse thoracic aorta with similar Emax values (53.9 and 51.9% of phenylephrine-induced precontraction), although the EC50 of LPA- and VPC31143-induced vasorelaxations were different (400 vs. 15 nM, respectively). Mechanical removal of the endothelium or genetic deletion of endothelial nitric oxide synthase (eNOS) not only diminished vasorelaxation by LPA or VPC31143 but converted it to vasoconstriction. Freshly isolated mouse aortic endothelial cells expressed LPA1, LPA2, LPA4 and LPA5 transcripts. The LPA1,3 antagonist Ki16425, the LPA1 antagonist AM095, and the genetic deletion of LPA1, but not that of LPA2, abolished LPA-induced vasorelaxation. Inhibition of the phosphoinositide 3 kinase-protein kinase B/Akt pathway by wortmannin or MK-2206 failed to influence the effect of LPA. However, pharmacological inhibition of phospholipase C (PLC) by U73122 or edelfosine, but not genetic deletion of PLCε, abolished LPA-induced vasorelaxation and indicated that a PLC enzyme, other than PLCε, mediates the response. In summary, the present study identifies LPA as an endothelium-dependent vasodilator substance acting via LPA1, PLC, and eNOS.

Lysophosphatidic Acid Signaling in the Nervous System

“…An early report, using a piglet model of intracranial hematoma demonstrated that LPA exposure produces dose-dependent vasoconstriction, which is reminiscent of that produced by hemorrhage (Tigyi et al, 1995). More recently, LPA has been found to mediate vasodilation via LPA 1 , phospholipase C, and endothelial nitric oxide synthase (Ruisanchez et al, 2014). LPA overexposure has been reported to increase BBB permeability (On et al, 2013; Yu et al, 2014), as may occur during pathological conditions like stroke.…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…Interestingly, increased LPA levels can rapidly and reversibly increase blood brain barrier permeability (80), suggesting a concentration-dependent mechanism. Finally, LPA can also regulate vascular tone, such as posthemorrhagic vasoconstriction in cerebral microvasculature (81) or vasodilation in the thoracic aorta (82). These opposing actions may be context dependent.…”

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

“…53 Micromolar levels of LPA may induce a vasoconstrictive response 54 in medial SMCs under high shear stresses, but lower doses cause endothelium-dependent vasodilation via endothelial nitric oxide synthase and phospholipase activity. 55 VEGF is perhaps the most widely studied proangiogenic molecule whose activity has been targeted as a therapeutic for initiating neovascularization and for blocking tumor growth. S1P has also been touted as a complete angiogenic molecule given its contributions at both early stages of angiogenesis and later stages of neovessel stabilization.…”