application) The importance of the endothelial cell lining of the blood vessel in the regulation of vascular tone is clearly established. Hormones such as acetylcholine, substance P, and bradykinin relax blood vessels in the presence of the endothelium but not in its absence. The relaxation is attributed to the release of EDRF. There is evidence for multiple EDRFs. One is nitric oxide, (NO-EDRF). In addition, there is an EDRF released by arachidonic acid (AA-EDRF) that is not PGI2, but a lipoxygenase metabolite. The investigators have identified this AA-EDRF as a metabolite of 15-lipoxygenase 11,14,15-trihydroxyeicosatrienoic acid (11,14,15-THETA) using bioassay, HPLC, and gas chromatography/mass spectrometry. 11-H-14,15-EETA is thought to be a precursor of 11,14,15-THETA. 11-H-14,15-EETA and 11,14,15-THETA relax the rabbit aorta and one or both represent AA-EDRF. The proposed studies will test the hypothesis that arachidonic acid is metabolized by the endothelium to vasodilator eicosanoids 11-H,14,15-EETA and 11,14,15-THETA that are involved in the regulation of vascular tone and contribute to the action of vasoactive hormones. Studies will be conducted in isolated blood vessels, smooth muscle cells and ECs. Using chemical, analytical, biochemical and pharmacological approaches the proposed experiments will: 1) determine if 11,14,15-EETA is produced by the aorta and ECs and determine the stereochemistry of 11,14,15-THETA. Experiments will compare the vasodilator activity of the THETA and HEETA, their stereo isomers; 2) develop an assay for 11,14,15-THETA and possibly 11-H-14-15-EETA and investigate the regulation of their release by vasoactive agents. The effect of inhibitors of arachidonic acid metabolism on release will be determined. This quantitative information will be combined with physiological and pharmacological studies to determine the contribution of the metabolites to vascular tone and the activity of vasoactive hormones; 3) study the biosynthetic pathway for 11,14,15-EETA and 11,14,15-THETA formation using purified enzymes, transfected cells, antibodies and inhibitors; and 4) investigate the mechanism by which 11,14,15-EETA and 11,14,15-THETA dilate smooth muscle.
| Siangjong, L; Goldman, D H; Kriska, T et al. (2017) Vascular hepoxilin and trioxilins mediate vasorelaxation through TP receptor inhibition in mouse arteries. Acta Physiol (Oxf) 219:188-201 |
| Kriska, Tamas; Cepura, Cody; Gauthier, Kathryn M et al. (2014) Role of macrophage PPAR? in experimental hypertension. Am J Physiol Heart Circ Physiol 306:H26-32 |
| Kriska, Tamas; Cepura, Cody; Siangjong, Lawan et al. (2013) Effect of human 15-lipoxygenase-1 metabolites on vascular function in mouse mesenteric arteries and hearts. Prostaglandins Other Lipid Mediat 106:8-15 |
| Siangjong, Lawan; Gauthier, Kathryn M; Pfister, Sandra L et al. (2013) Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries. Am J Physiol Heart Circ Physiol 304:H382-92 |
| Campbell, William B; Gauthier, Kathryn M (2013) Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway. J Cardiovasc Pharmacol 61:176-87 |
| Kriska, Tamas; Cepura, Cody; Magier, Devora et al. (2012) Mice lacking macrophage 12/15-lipoxygenase are resistant to experimental hypertension. Am J Physiol Heart Circ Physiol 302:H2428-38 |
| Aggarwal, Nitin T; Gauthier, Kathryn M; Campbell, William B (2012) Endothelial nitric oxide and 15-lipoxygenase-1 metabolites independently mediate relaxation of the rabbit aorta. Vascul Pharmacol 56:106-12 |
| Pfister, Sandra L; Nithipatikom, Kasem; Campbell, William B (2011) Role of superoxide and thromboxane receptors in acute angiotensin II-induced vasoconstriction of rabbit vessels. Am J Physiol Heart Circ Physiol 300:H2064-71 |
| Gauthier, Kathryn M; Goldman, Daniel H; Aggarwal, Nitin T et al. (2011) Role of arachidonic acid lipoxygenase metabolites in acetylcholine-induced relaxations of mouse arteries. Am J Physiol Heart Circ Physiol 300:H725-35 |
| Pfister, Sandra L; Gauthier, Kathryn M; Campbell, William B (2010) Vascular pharmacology of epoxyeicosatrienoic acids. Adv Pharmacol 60:27-59 |
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