Lysophosphatidic acid (LPA) is a bioactive lipid mediator, which exerts its effects
via
its six specific GPCRs mediating important physiological and pathophysiological responses,
like platelet activation or cell-migration. During vascular injury or rupture of an
atherosclerotic plaque, the consequential platelet activation leads to the release
of mainly
polyunsaturated LPAs, especially 18:2 LPA. In hypertension and acute myocardial infarction,
the level of these polyunsaturated LPAs is also elevated. Based on the previous results
of our
research group, LPA1 receptor activation by the 18:2 LPA evokes cyclooxygenase 1 activation
with consequential thromboxane A2 (TXA2) release, and vasoconstriction.
In this study we further analyzed the signaling mechanisms underlying the constrictor
effect of 18:2 LPA.
We did experiments in aortas isolated from Bl6 mice. Our main method was the
measurement of the vascular tone with myography. The endothelium, and in some cases
the
adventitia as well, was mechanically removed and the 18:2 LPA was administered on
the
resting tone. TXA2 release of the vessels was measured by ELISA. Primary vascular
cells were
isolated from different layers of the aorta and their intracellular Ca2+ signal upon
LPA
administration was determined. qPCR was used to measure the expression of the LPA1
receptor in the lamina media and adventitia.
According to our results, removal of the adventitia significantly decreases the elicited
vasoconstriction, and results in a complete loss of thromboxane release. In agreement
with
this, LPA1 receptor is predominantly expressed in the adventitial layer, as removal
of the
adventitia resulted in diminished expression of Lpar1. Staining of the LPA1 receptor
was only
present in the adventitial layer, but not in the lamina media. Primary isolated vascular
smooth muscle cells exhibited negligible Ca2+ signal upon administration of 18:2 LPA,
however a subpopulation of adventitial cells showed marked intracellular Ca2+ increase
when stimulated by 18:2 LPA.
In conclusion, LPA 18:2 has strong vasoconstrictor activity, due to its ability to
increase LPAR1–Gi–COX mediated thromboxane release from the adventitia, highlighting
the
significance of this layer in the regulation of vasomotion.
