{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:56:01Z","timestamp":1788270961276,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Recent evidence suggests that the reason Extra Virgin Olive Oil (EVOO) lowers blood pressure and reduces the risk of developing hypertension is partly due to minor components of EVOO, such as phenols. However, little is still known about the mechanism(s) through which EVOO phenols mediate anti-hypertensive effects. The aim of the present study was to investigate the mechanisms of action of EVOO phenols on mesenteric resistance arteries. A pressure myograph was used to test the effect of EVOO phenols on isolated mesenteric arteries in the presence of specific inhibitors of: (1) BKca channels (Paxillin, 10\u22125 M); (2) L-type calcium channels (Verapamil, 10\u22125 M); (3) Ryanodine receptor, RyR (Ryanodine, 10\u22125 M); (4) inositol 1,4,5-triphosphate receptor, IP3R, (2-Aminoethyl diphenylborinate, 2-APB, 3 \u00d7 10\u22123 M); (5) phospholipase C, PLC, (U73122, 10\u22125 M), and (6) GPCR-G\u03b1i signaling, (Pertussis Toxin, 10\u22125 M). EVOO phenols induced vasodilation of mesenteric arteries in a dose-dependent manner, and this effect was reduced by pre-incubation with Paxillin, Verapamil, Ryanodine, 2-APB, U73122, and Pertussis Toxin. Our data suggest that EVOO phenol-mediated vasodilation requires activation of BKca channels potentially through a local increase of subcellular calcium microdomains, a pivotal mechanism on the base of artery vasodilation. These findings provide novel mechanistic insights for understanding the vasodilatory properties of EVOO phenols on resistance arteries.<\/jats:p>","DOI":"10.3390\/biom11020137","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T11:49:40Z","timestamp":1611229780000},"page":"137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Extra Virgin Olive Oil Phenols Vasodilate Rat Mesenteric Resistance Artery via Phospholipase C (PLC)-Calcium Microdomains-Potassium Channels (BKCa) Signals"],"prefix":"10.3390","volume":"11","author":[{"given":"Rossana","family":"D\u2019Agostino","sequence":"first","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Barberio","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariacarmela","family":"Gatto","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Tropea","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"},{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK"},{"name":"Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, St. Mary\u2019s Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6345-7508","authenticated-orcid":false,"given":"Maria","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3736-0205","authenticated-orcid":false,"given":"Maurizio","family":"Mandal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"},{"name":"Department of Obstetrics, Gynecology and Reproductive Science, University of Vermont, Burlington, VT 05405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Oparil, S., Acelajado, M.C., Bakris, G.L., Berlowitz, D.R., C\u00edfkov\u00e1, R., Dominiczak, A.F., Grassi, G., Jordan, J., Poulter, N.R., and Rodgers, A. (2018). Hypertension. Nat. Rev. Dis Primers, 4.","DOI":"10.1038\/nrdp.2018.14"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jacc.2017.04.052","article-title":"Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015","volume":"70","author":"Roth","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1056\/NEJM200007063430103","article-title":"Primary prevention of coronary heartdisease in women through diet and lifestyle","volume":"343","author":"Stampfer","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1001\/jama.292.12.1433","article-title":"Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: The HALE project","volume":"292","author":"Knoops","year":"2004","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gaforio, J.J., Visioli, F., Alarc\u00f3n-de-la-Lastra, C., Casta\u00f1er, O., Delgado-Rodr\u00edguez, M., Fit\u00f3, M., Hern\u00e1ndez, A.F., Huertas, J.R., Mart\u00ednez-Gonz\u00e1lez, M.A., and Menendez, J.A. (2019). Virgin Olive Oil and Health: Summary of the III International Conference on Virgin Olive Oil and Health Consensus Report, JAEN (Spain) 2018. Nutrients, 11.","DOI":"10.3390\/nu11092039"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"933","DOI":"10.2174\/1381612013397654","article-title":"Mediterranean diet and health: Biological importance of olive oil","volume":"7","author":"Barranco","year":"2001","journal-title":"Curr. Pharm. Des."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1002\/mnfr.200600305","article-title":"Vasculoprotective potential of olive oil components","volume":"51","author":"Carluccio","year":"2007","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/1871530317666171114121533","article-title":"Extra Virgin Olive Oil and Cardiovascular Diseases: Benefits for Human Health","volume":"18","author":"Nocella","year":"2018","journal-title":"Endocr. Metab. Immune Disord. Drug Targets."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.clnu.2004.02.004","article-title":"Virgin olive oil reduces blood pressure in hypertensive elderly subjects","volume":"23","author":"Perona","year":"2004","journal-title":"Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1056\/NEJMoa1200303","article-title":"Primary prevention of cardiovascular disease with a Mediterranean diet","volume":"368","author":"Estruch","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1161\/HYPERTENSIONAHA.113.03353","article-title":"Mediterranean diet reduces 24-hour ambulatory blood pressure, blood glucose, and lipids: One-year randomized, clinical trial","volume":"64","author":"Domenech","year":"2014","journal-title":"Hypertension"},{"key":"ref_12","unstructured":"Boskou, D., Tsimidou, M., and Blekas, G. (2006). Polar Phenolic Compounds. Olive Oil: Chemistry and Technology, The American Oil Chemists\u2019 Society. [2nd ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/antiox3010001","article-title":"Biological Activities of Phenolic Compounds of Extra Virgin Olive Oil","volume":"3","author":"Servili","year":"2013","journal-title":"Antioxidants"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Romani, A., Ieri, F., Urciuoli, S., Noce, A., Marrone, G., Nediani, C., and Bernini, R. (2019). Health Effects of Phenolic Compounds Found in Extra-Virgin Olive Oil, By-Products, and Leaf of Olea europaea L.. Nutrients, 11.","DOI":"10.3390\/nu11081776"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1161\/01.HYP.0000107778.85528.b5","article-title":"2-Hydroxyoleic Acid: A new Hypotensive Molecule","volume":"43","author":"Alemany","year":"2004","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13811","DOI":"10.1073\/pnas.0807500105","article-title":"Oleic acid content is responsible for the reduction in blood pressure induced by olive oil","volume":"105","author":"Benet","year":"2008","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1096\/fj.09-148452","article-title":"In vivo nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet: A randomized controlled trial","volume":"24","author":"Konstantinidou","year":"2010","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.atherosclerosis.2004.12.036","article-title":"Antioxidant effect of virgin olive oil in patients with stable coronary heart disease: A randomized, crossover, controlled, clinical trial","volume":"181","author":"Fito","year":"2005","journal-title":"Atherosclerosis"},{"key":"ref_19","first-page":"1299","article-title":"Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension","volume":"25","author":"Miranda","year":"2012","journal-title":"Am. J. Hypertens."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"D\u2019Agostino, R., Barberio, L., Gatto, M., Muzzalupo, I., and Mandal\u00e0, M. (2020). Extra Virgin Olive Oil Phenols Dilate the Rat Mesenteric Artery by Activation of BKCa2+ Channels in Smooth Muscle Cells. Molecules, 25.","DOI":"10.3390\/molecules25112601"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1021\/jf00021a019","article-title":"Simple and hydrolyzable phenolic compounds in virgin olive oil. 1. Their extraction, separation, and quantitative and semiquantitative evaluation by HPLC","volume":"40","author":"Montedoro","year":"1992","journal-title":"J. Agr. Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1021\/jf0013205","article-title":"Determination of phenols, flavones, and lignans in virgin olive oils by solid-phase extraction and high-performance liquid chromatography with diode array ultraviolet detection","volume":"49","author":"Mateos","year":"2001","journal-title":"J. Agr. Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1159\/000178465","article-title":"Influence of Constriction, Wall Tension, Smooth Muscle Activation and Cellular Deformation on Rat Resistance Artery Vasodilator Reactivity","volume":"29","author":"Colton","year":"2012","journal-title":"Cell Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1161\/01.HYP.27.1.25","article-title":"Antihypertensive therapy prevents endothelial dysfunction in chronic nitric oxide deficiency. Effect of verapamil and trandolapril","volume":"27","author":"Takase","year":"1996","journal-title":"Hypertension"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H981","DOI":"10.1152\/ajpheart.00866.2013","article-title":"Opposing roles of smooth muscle BK channels and ryanodine receptors in the regulation of nerve-evoked constriction of mesenteric resistance arteries","volume":"306","author":"Krishnamoorthy","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.pharep.2013.11.005","article-title":"Mechanisms of the sarcoplasmic reticulum Ca2+ release induced by P2X receptor activation in mesenteric artery myocytes","volume":"66","author":"Sukhanova","year":"2014","journal-title":"Pharmacol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1113\/JP274797","article-title":"Vasoconstrictor stimulus determines the functional contribution of myoendothelial feedback to mesenteric arterial tone","volume":"596","author":"Wei","year":"2018","journal-title":"J Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1111\/jcmm.14994","article-title":"Prenatal hypoxia inhibited propionate-evoked BK channels of mesenteric artery smooth muscle cells in offspring","volume":"24","author":"Zhang","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2515\/therapie:2003019","article-title":"Effects of virgin olive oil phenolic compounds on LDL oxidation and vasorelaxation activity","volume":"58","author":"Benkhalti","year":"2003","journal-title":"Therapies"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.jff.2016.03.024","article-title":"Involvement of endothelium in the vasorelaxant effects of 3,4-DHPEA-EA and 3,4-DHPEA-EDA, two major functional bioactives in olive oil","volume":"23","author":"Segade","year":"2016","journal-title":"J. Funct. Foods"},{"key":"ref_31","first-page":"3","article-title":"Reduced Ca2+ Spark Activity after Subarachnoid Hemorrhage Disables BK Channel Control of Cerebral Artery Tone","volume":"31","author":"Koide","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1080\/19336950.2019.1688910","article-title":"Elementary calcium signaling in arterial smooth muscle","volume":"13","author":"Fan","year":"2019","journal-title":"Channels"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Khavandi, K., Baylie, R.A., Sugden, S.A., Ahmed, M., Csato, V., Eaton, P., Hill-Eubanks, D.C., Bonev, A.D., Nelson, M.T., and Greenstein, A.S. (2016). Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels. Sci. Signal., 9.","DOI":"10.1126\/scisignal.aaf6625"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1161\/CIRCRESAHA.111.258145","article-title":"Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels","volume":"110","author":"Dabertrand","year":"2012","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1113\/jphysiol.2011.222083","article-title":"Function and expression of ryanodine receptors and inositol 1,4,5-trisphosphate receptors in smooth muscle cells of murine feed arteries and arterioles","volume":"590","author":"Westcott","year":"2012","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"H1616","DOI":"10.1152\/ajpheart.00728.2010","article-title":"Heterogeneous function of ryanodine receptors, but not IP3 receptors, in hamster cremaster muscle feed arteries and arterioles","volume":"300","author":"Westcott","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1097\/HJH.0000000000002457","article-title":"Chronic exercise mediates epigenetic suppression of L-type Ca2+ channel and BKCa channel in mesenteric arteries of hypertensive rats","volume":"38","author":"Zhang","year":"2020","journal-title":"J. Hypertens."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"36750","DOI":"10.1074\/jbc.M113.511485","article-title":"Caveolin-1 facilitates the direct coupling between large conductance Ca2+-activated K+ (BKCa) and Cav1.2 Ca2+ channels and their clustering to regulate membrane excitability in vascular myocytes","volume":"288","author":"Suzuki","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"C200","DOI":"10.1152\/ajpcell.00103.2006","article-title":"Inhibition of G\u03b1q-dependent PLC-beta1 activity by PKG and PKA is mediated by phosphorylation of RGS4 and GRK2","volume":"292","author":"Huang","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2013.01.006","article-title":"Mechanisms of vasorelaxation induced by oleoylethanolamide in the rat small mesenteric artery","volume":"702","author":"Hiley","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1096\/fj.13-234997","article-title":"Lysophosphatidic acid induces vasodilation mediated by LPA1 receptors, phospholipase C, and endothelial nitric oxide synthase","volume":"28","author":"Ruisanchez","year":"2014","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1111\/bph.14762","article-title":"Endothelial TRPV4 channels modulate vascular tone by Ca2+ -induced Ca2+ release at inositol 1,4,5-trisphosphate receptors","volume":"176","author":"Heathcote","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8532","DOI":"10.1073\/pnas.1608859113","article-title":"Maintenance of normal blood pressure is dependent on IP3R1-mediated regulation of eNOS","volume":"113","author":"Yuan","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1469-7793.1998.211br.x","article-title":"Ryanodine receptors regulate arterial diameter and wall [Ca2+] in cerebral arteries of rat via Ca2+-dependent K+ channels","volume":"508","author":"Knot","year":"1998","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.20517\/2574-1209.2018.44","article-title":"A current view of G protein-coupled receptor - mediated signaling in pulmonary hypertension: Finding opportunities for therapeutic intervention","volume":"2","author":"Strassheim","year":"2018","journal-title":"Vessel. 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