{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T20:06:01Z","timestamp":1771617961064,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Seventh Framework Programme","award":["601852"],"award-info":[{"award-number":["601852"]}]},{"name":"Icelandic Research Fund","award":["163369-051"],"award-info":[{"award-number":["163369-051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acetylsalicylic acid (aspirin) exhibits a broad range of activities, including analgesic, antipyretic, and antiplatelet properties. Recent clinical studies also recommend aspirin prophylaxis in women with a high risk of pre-eclampsia, a major complication of pregnancy characterized by hypertension. We investigated the effect of aspirin on mesenteric resistance arteries and found outdiscovered the molecular mechanism underlying this action. Aspirin (10\u221212\u201310\u22126 M) was tested on pregnant rat mesenteric resistance arteries by a pressurized arteriography. Aspirin was investigated in the presence of several inhibitors of: (a) nitric oxide synthase (L-NAME 2 \u00d7 10\u22124 M); (b) cyclooxygenase (Indomethacin, 10\u22125 M); (c) Ca2+-activated K+ channels (Kca): small conductance (SKca, Apamin, 10\u22127 M), intermediate conductance (IKca, TRAM34, 10\u22125 M), and big conductance (BKca, paxilline, 10\u22125 M); and (d) endothelial-derived hyperpolarizing factor (high KCl, 80 mM). Aspirin caused a concentration-dependent vasodilation. Aspirin-vasodilation was abolished by removal of endothelium or by high KCl. Furthermore, preincubation with either apamin plus TRAM-34 or paxillin significantly attenuated aspirin vasodilation (p &lt; 0.05). For the first time, we showed that aspirin induced endothelium-dependent vasodilation in mesenteric resistance arteries through the endothelial-derived hyperpolarizing factor (EDHF) and calcium-activated potassium channels. By activating this molecular mechanism, aspirin may lower peripheral vascular resistance and be beneficial in pregnancies complicated by hypertension.<\/jats:p>","DOI":"10.3390\/ijms221810162","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Endothelium-Derived Hyperpolarizing Factor (EDHF) Mediates Acetylsalicylic Acid (Aspirin) Vasodilation of Pregnant Rat Mesenteric Arteries"],"prefix":"10.3390","volume":"22","author":[{"given":"Helga","family":"Helgad\u00f3ttir","sequence":"first","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"},{"name":"Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Tropea","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-9752","authenticated-orcid":false,"given":"Sveinbj\u00f6rn","family":"Gizurarson","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Schr\u00f6r, K. (2009). General aspects (History and Chemistry). Acetylsalicylic Acid, Wiley-VCH.","DOI":"10.1002\/9783527625994"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s43441-020-00156-w","article-title":"A Systematic Review of the Efficacy and Safety of Aspirin When Delivered at Different Medication Times for the Primary and Secondary Prevention of Cardiovascular and Cerebrovascular Diseases","volume":"54","author":"Zhou","year":"2020","journal-title":"Innov. Regul. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1056\/NEJMoa1704559","article-title":"Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia","volume":"377","author":"Rolnik","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Walsh, S.W., and Strauss, J.F. (2021). The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136985"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"214365","DOI":"10.1155\/2011\/214365","article-title":"Maternal preeclampsia and neonatal outcomes","volume":"2011","author":"Backes","year":"2011","journal-title":"J. Pregnancy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11906-017-0757-7","article-title":"Pathophysiology and Current Clinical Management of Preeclampsia","volume":"19","author":"Amaral","year":"2017","journal-title":"Curr. Hypertens Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1097\/AOG.0b013e3181e9322a","article-title":"Prevention of Preeclampsia and Intrauterine Growth Restriction with Aspirin Started in Early Pregnancy: A Meta-Analysis","volume":"116","author":"Bujold","year":"2010","journal-title":"Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.ajog.2017.11.561","article-title":"Aspirin for the prevention of preterm and term preeclampsia: Systematic review and metaanalysis","volume":"218","author":"Roberge","year":"2018","journal-title":"Am. J. Obs. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/uog.6215","article-title":"Low-dose aspirin reduces uteroplacental vascular impedance in early and mid gestation in IVF and ICSI patients: A randomized, placebo-controlled double-blind study","volume":"32","author":"Haapsamo","year":"2008","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.thromres.2018.08.010","article-title":"The effect of aspirin on placental vessels reactivity using the ex-vivo placental perfusion model","volume":"170","author":"Kovo","year":"2018","journal-title":"Thromb. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/cvr\/cvp084","article-title":"Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA\/Rho-kinase activation","volume":"83","author":"Ying","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1161\/01.CIR.0000140985.89766.CB","article-title":"Aspirin-triggered, cyclooxygenase-2-dependent lipoxin synthesis modulates vascular tone","volume":"110","author":"Hollenberg","year":"2004","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.preghy.2019.01.001","article-title":"Aspirin causes endothelium-dependent vasodilation of resistance arteries from non-gravid and gravid rats","volume":"15","author":"Helgadottir","year":"2019","journal-title":"Pregnancy Hypertens"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.jacc.2004.08.071","article-title":"Aspirin administered at bedtime, but not on awakening, has an effect on ambulatory blood pressure in hypertensive patients","volume":"46","author":"Hermida","year":"2005","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3233\/CH-2011-1440","article-title":"Influence of acetylsalicylic acid (Aspirin) on cutaneous microcirculation","volume":"50","author":"Mrowietz","year":"2012","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev-physiol-020518-114435","article-title":"Plasticity of the Maternal Vasculature During Pregnancy","volume":"81","author":"Osol","year":"2019","journal-title":"Annu. Rev. Physiol."},{"key":"ref_17","first-page":"90","article-title":"Assessment of total vascular resistance and total body water in normotensive women during the first trimester of pregnancy in order to predict hypertensive complications","volume":"3","author":"Scala","year":"2013","journal-title":"Pregnancy Hypertens. Int. J. Women\u2019s Cardiovasc. Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1152\/ajpregu.00762.2001","article-title":"Vascular mechanisms of increased arterial pressure in preeclampsia: Lessons from animal models","volume":"283","author":"Khalil","year":"2002","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"302","DOI":"10.2174\/1874192401004010302","article-title":"The endothelium and its role in regulating vascular tone","volume":"4","author":"Sandoo","year":"2010","journal-title":"Open Cardiovasc. Med. J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kr\u00fcger-Genge, A., Blocki, A., Franke, R.P., and Jung, F. (2019). Vascular Endothelial Cell Biology: An Update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184411"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1055\/s-2007-1016248","article-title":"Endothelial dysfunction in preeclampsia","volume":"16","author":"Roberts","year":"1998","journal-title":"Semin. Reprod. Endocrinol."},{"key":"ref_22","first-page":"183","article-title":"Peripheral microcirculation during pregnancy and in women with pregnancy induced hypertension","volume":"24","author":"Ohlmann","year":"2001","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"391","DOI":"10.14740\/jocmr3368w","article-title":"Sidestream Dark Field Imaging of the Microcirculation to Assess Preeclampsia Microvascular Dysfunction","volume":"10","author":"Pelland","year":"2018","journal-title":"J. Clin. Med. Res."},{"key":"ref_24","unstructured":"Klabunde, R.E. (2021). Cardiovascular Physiology Concepts, Wolters Kluwer. [3rd ed.]."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/bja\/77.1.50","article-title":"Determinants of splanchnic blood flow","volume":"77","author":"Takala","year":"1996","journal-title":"Br. J. Anaesth."},{"key":"ref_26","first-page":"H41","article-title":"Effect of pregnancy on contraction and endothelium-mediated relaxation of renal and mesenteric arteries","volume":"267","author":"Kim","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1093\/humrep\/13.5.1361","article-title":"Pregnancy augments nitric oxide-dependent dilator response to acetylcholine in the human uterine artery","volume":"13","author":"Nelson","year":"1998","journal-title":"Hum. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R510","DOI":"10.1152\/ajpregu.00458.2007","article-title":"Endothelium-derived hyperpolarizing factor in preeclampsia: Heterogeneous contribution, mechanisms, and morphological prerequisites","volume":"294","author":"Luksha","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s13167-017-0099-1","article-title":"Endothelial dysfunction in cardiovascular disease and Flammer syndrome-similarities and differences","volume":"8","author":"Barthelmes","year":"2017","journal-title":"EPMA J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"533.e1","DOI":"10.1016\/j.ajog.2015.06.043","article-title":"Circulating endothelial cell number and markers of endothelial dysfunction in previously preeclamptic women","volume":"213","author":"Tuzcu","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_31","first-page":"372","article-title":"Endothelial dysfunction and preeclampsia: Role of oxidative stress","volume":"5","author":"Prada","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1146\/annurev.med.59.110106.214058","article-title":"Preeclampsia and angiogenic imbalance","volume":"59","author":"Maynard","year":"2008","journal-title":"Annu. Rev. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1161\/01.HYP.35.1.367","article-title":"Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat","volume":"35","author":"Crews","year":"2000","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1113\/jphysiol.1994.sp020449","article-title":"Characterization of EDHF as a cytochrome P450-derived arachidonic acid metabolite in mammals","volume":"481","author":"Hecker","year":"1994","journal-title":"J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1161\/01.RES.0000019756.88731.83","article-title":"Involvement of myoendothelial gap junctions in the actions of endothelium-derived hyperpolarizing factor","volume":"90","author":"Sandow","year":"2002","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/24388","article-title":"K+ is an endothelium-derived hyperpolarizing factor in rat arteries","volume":"396","author":"Edward","year":"1998","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/j.1476-5381.2009.00132.x","article-title":"Endothelial Ca2+ -activated K+ channels in normal and impaired EDHF-dilator responses-relevance to cardiovascular pathologies and drug discovery","volume":"157","author":"Grgic","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"H216","DOI":"10.1152\/ajpheart.01383.2005","article-title":"Regional heterogeneity in acetylcholine-induced relaxation in rat vascular bed: Role of calcium-activated K+ channels","volume":"291","author":"Hilgers","year":"2006","journal-title":"Am. J. Physiol. Heart Cir. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1159\/000329821","article-title":"Endothelial-derived hyperpolarization factor (EDHF) contributes to PLGF-induced dilation of mesenteric resistance arteries from pregnant rats","volume":"49","author":"Gokina","year":"2012","journal-title":"J. Vasc. Res."},{"key":"ref_40","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."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:48Z","timestamp":1760166168000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,21]]},"references-count":40,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810162"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,21]]}}}