RELATIONSHIP BETWEEN PHOSPHOLIPASE-D ACTIVATION AND ENDOTHELIAL VASOMOTOR DYSFUNCTION IN RABBIT AORTA

Lysophosphatidylcholine (lysoPC) causes endothelial vasomotor dysfunct ion in isolated blood vessels, although the signaling pathways involve d in this effect remain to be established. Although lysoPC stimulated phospholipase D (PLD) activity in cultured endothelial cells, the role of PLD in the vascular effects of lysoPC remains unclear. This study investigated the hypothesis that PLD is involved in lysoPC-induced end othelial vasomotor dysfunction in isolated rabbit aorta. LysoPC (3-30 mu M) stimulated vascular PLD activity and inhibited endothelium-depen dent vasorelaxation to acetylcholine within an identical concentration range. In contrast, lysoPC-induced inhibition of vasorelaxation was n ot prevented by the selective protein kinase C (PKC) inhibitor, GF1092 03X (3 mu M), which suggested that this enzyme was not involved in the endothelial vasomotor dysfunction produced by lysoPC. The ability of two other lysophospholipids, lyso-platelet-activating factor (3-30 mu M) and lysophosphatidylserine (10-30 mu M) to induce endothelial vasom otor dysfunction was also associated closely with their ability to sti mulate vascular PLD activity. Parallel stimulation of PLD activity and inhibition of acetylcholine-induced relaxation was also observed with orthovanadate (0.1-3 mM), which suggested that the association betwee n PLD activation and endothelial vasomotor dysfunction was not a pheno menon particular to lysophospholipids. The magnitude of PLD stimulatio n and the extent of endothelial dysfunction induced by these diverse s timuli were highly correlated (r(2) = 0.88). These observations sugges t that the PLD signal transduction pathway is important in the endothe lial vasomotor dysfunction produced by lysophospholipids and perhaps o ther agents.