title: Relationship between phospholipase D activation and endothelial vasomotor dysfunction in rabbit aorta.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 47628, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Cox
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: 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*
chemical_list: D008244:Lysophosphatidylcholines; D009599:Nitroprusside; D014638:Vanadates; D011493:Protein Kinase C; D010739:Phospholipase D