Lysophosphatidic acid* (LPA) is produced by a variety of activated
cell types and acts as an intercellular mediator of processes
associated with inflammation and repair including platelets
aggregation, and smooth muscle and fibroblast proliferation.
However no previous studies have examined the effects of LPA
on endothelial cell leukocyte interactions. We have examined
the ability of LPA to activate human aortic endothelial cells
(HAEC) to bind monocytes, neutrophils, and HL60 cells (a neutrophil
surrogate). Treatment of HAEC for 4 hours with 10 um LPA caused
an increase in the binding of monocytes, neutrophils, and HL60.
LPA but not phosphatidic acid dose-dependently increased E-selectin
and vascular cell adhesion molecule-1 (VCAM-1) cell surface
expression. We performed several studies to characterize the
receptor mediating the LPA effect. We demonstrate that at least
five potential LPA receptors are expressed by HAEC: EDG-1, -3,
-4, and -5 as well as PSP24. Cyclic phosphate-containing phosphatidic
acid analogue, an agonist for the type 3 low affinity LPA receptor,
was not effective in activating HAEC to bind leukocytes, excluding
a role for this receptor. The selective receptor antagonists
N-palmitoyl- palmitoylserinephosphate serinephosphate
and N-palmitoyl-tyrosinephosphate
(which inhibits PSP24) completely inhibited LPAinduced
VCAM expression; however these antagonists inhibited E-selectin
expression by only 30%, suggesting a role for at least one additional
LPA receptor mediating E-selectin expression. We propose that
EDG-1 might be the second receptor, because this receptor, when
expressed in HEK293 cells, similarly to the PSP24 receptor,
caused ERK activation to nanomolar concentration of LPA. Exposure
of HAEC to sphingosine-1-phosphate*, another EDG-1 receptor
agonist, increased surface expression of E-selectin and to a
much smaller extent VCAM-1. The effects of both LPA and sphingosine-1-phosphate
on the induction of both VCAM-1 and E-selectin expression was
abolished by pretreatment with pertussis toxin suggesting that
both LPA receptors in HAEC couple to a Gi pathway. These findings
reveal an important and novel role for LPA and its receptors
in inflammatory processes. |
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