Research Report 2010 - MDC

Epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoicacids (DHETs) stimulate the productionof nitric oxide (NO) in endothelial cellsto induce vasorelaxation. Red blood cells are arich source of EETs and may utilize this mechanismto produce vasorelaxation in the microcirculation(from the cover page of ArteriosclerThromb Vasc Biol. 2009 Jan;29(1)).sure in angiotensin II-infused hypertension, but not inL-NAME-induced hypertension. Blood pressure andEDHF responses were similar in L-NAME-treated sEH+/+ and -/- mice. The data indicate that the EDHFresponse in mice is caused by hydrogen peroxide, butnot by P450 eicosanoids. Moreover, P450 eicosanoidsare vasodilatory, largely through their ability to activateendothelial NO synthase (eNOS) and NO release.Endothelial-derived contracting factors (EDCFs)Hypertension and vascular dysfunction result in theincreased release of EDCFs, whose identity is poorlydefined. The Gollasch team tested the hypothesis thatendothelial cyclooxygenase (COX)-2 can generateEDCFs and identified the possible EDCF candidate. Theyshowed that endothelium-dependent contractionswere triggered by acetylcholine (ACh) after inhibitionof nitric oxide production and they were abolished byCOX-2 but not COX-1 inhibitors or by thromboxaneprostanoidreceptor antagonists. The cation channelblocker, 2-amino-ethoxydiphenyl borate eliminatedendothelium-dependent contractions and ACh-stimulatedrises in endothelial cell [Ca(2+)](i). RT-PCR andWestern blotting showed COX-2 expression mainly inthe endothelium. Enzyme immunoassay and high-performanceliquid chromatography-coupled mass spectrometryshowed release of prostaglandin(PG)F(2alpha) and prostacyclin (PGI(2)) increased byACh; only PGF(2alpha) caused contraction at relevantconcentrations. COX-2 expression, ACh-stimulated contractions,and vascular sensitivity to PGF(2alpha) wereaugmented in aortae from aged hamsters. Humanrenal arteries also showed thromboxane-prostanoidreceptor-mediated ACh- or PGF(2alpha)-induced contractionsand COX-2-dependent release of PGF(2alpha).The results support a critical role of COX-2 in endothelium-dependentcontractions in this species with anincreased importance during aging and, possibly, asimilar relevance in humans.Selected publicationsEssin, K, Gollasch, M, Rolle, S, Weissgerber, P, Sausbier, M, Bohn, E,Autenrieth, IB, Ruth, P, Luft, FC, Nauseef, WM, Kettritz, R. (2009) BKchannels in innate immune functions of neutrophils and macrophages.Blood. 113, 1326-1331.Hercule, HC, Schunck, WH, Gross, V, Seringer, J, Leung, FP, Weldon, SM, daCosta Goncalves, ACh, Huang, Y, Luft, FC, Gollasch, M. (2009) Interactionbetween P450 eicosanoids and nitric oxide in the control of arterial tonein mice. Arterioscler Thromb Vasc Biol. 29, 54-60.Wong, SL, Leung, FP, Lau, CW, Au, CL, Yung, LM, Yao, X, Chen, ZY, Vanhoutte,PM, Gollasch, M, Huang, Y. (2009) Cyclooxygenase-2-derived prostaglandinF2alpha mediates endothelium-dependent contractions in theaortae of hamsters with increased impact during aging. Circ Res. 104,228-35.Hegner, B, Lange, M, Kusch, A, Essin, K, Sezer, O, Schulze-Lohoff, E, Luft, FC,Gollasch, M, Dragun, D. (2009) mTOR regulates vascular smooth musclecell differentiation from human bone marrow-derived mesenchymalprogenitors. Arterioscler Thromb Vasc Biol. 29, 232-238.Mederos, Y, Schnitzler, M, Storch, U, Meibers, S, Nurwakagari, P, Breit, A,Essin, K, Gollasch, M, Gudermann, T. (2008) Gq-coupled receptors asmechanosensors mediating myogenic vasoconstriction. EMBO J. 27,3092-3103.The Experimental and Clinical Research Center 215