Relationship between phospholipase D activation and endothelial vasomotor dysfunction in rabbit aorta.
Lysophosphatidylcholine (lysoPC) causes endothelial vasomotor dysfunction in isolated blood vessels, although the signaling pathways involved 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 endothelial vasomotor dysfunction in isolated rabbit aorta. LysoPC (3-30 microM) stimulated vascular PLD activity and inhibited endothelium-dependent vasorelaxation to acetylcholine within an identical concentration range. In contrast, lysoPC-induced inhibition of vasorelaxation was not prevented by the selective protein kinase C (PKC) inhibitor, GF109203X (3 microM), 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 microM) and lysophosphatidylserine (10-30 microM) to induce endothelial vasomotor dysfunction was also associated closely with their ability to stimulate 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 between PLD activation and endothelial vasomotor dysfunction was not a phenomenon particular to lysophospholipids. The magnitude of PLD stimulation and the extent of endothelial dysfunction induced by these diverse stimuli were highly correlated (r2 = 0.88). These observations suggest that the PLD signal transduction pathway is important in the endothelial vasomotor dysfunction produced by lysophospholipids and perhaps other agents.
Cox
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DA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 47628, USA.
Cohen
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D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D066298:In Vitro Techniques; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010739:Phospholipase D / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D011817:Rabbits; D015398:Signal Transduction; D014638:Vanadates / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D008244:Lysophosphatidylcholines; D009599:Nitroprusside; D014638:Vanadates; D011493:Protein Kinase C; D010739:Phospholipase D