{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:14:03Z","timestamp":1792034043021,"version":"4.4.0"},"reference-count":54,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The endothelin\u20101\u2010induced vasodilation in these PCOS subject, was dependent on the ET\n                            <jats:sub>B<\/jats:sub>\n                            R but was not NO\u2010dependent.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Endothelin\u20101 (ET\u20101) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE\u2010PCOS). The endothelin B receptor (ET\n                      <jats:sub>B<\/jats:sub>\n                      R) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE\u2010PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE\u2010PCOS (controls, 6 lean, 7 obese). Only obese AE\u2010PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVC\n                      <jats:sub>max<\/jats:sub>\n                      ) with laser Doppler flowmetry during low dose intradermal microdialysis ET\u20101 perfusions (1, 3, 4, 5 and 7\u00a0pmol) with either lactated Ringer solution alone, or with ET\n                      <jats:sub>B<\/jats:sub>\n                      R (BQ\u2010788), or nitric oxide (NO) inhibition (\n                      <jats:sc>l<\/jats:sc>\n                      \u2010NAME). Log[ET\u20101]\u2013%maxCVC dose\u2013response curves demonstrated reduced vasodilatory responses to ET\u20101 in lean AE\u2010PCOS (logED\n                      <jats:sub>50<\/jats:sub>\n                      , 0.59\u00a0\u00b1\u00a00.08)\n                      <jats:italic>versus<\/jats:italic>\n                      lean controls (logED\n                      <jats:sub>50<\/jats:sub>\n                      , 0.49\u00a0\u00b1\u00a00.09,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), but not compared to obese AE\u2010PCOS (logED\n                      <jats:sub>50<\/jats:sub>\n                      , 0.65\u00a0\u00b1\u00a00.09). ET\n                      <jats:sub>B<\/jats:sub>\n                      R inhibition decreased ET\u20101\u2010induced vasodilatation in AE\u2010PCOS women (logED\n                      <jats:sub>50<\/jats:sub>\n                      , 0.64\u00a0\u00b1\u00a00. 22,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). This was mechanistically observed at the cellular level, with ET\u20101\u2010induced, DAF\u2010FM\u2010measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor\u2010dependent manner. EE augmented the cutaneous vasodilating response to ET\u20101(logED\n                      <jats:sub>50<\/jats:sub>\n                      0.29\u00a0\u00b1\u00a00.21, 0.47\u00a0\u00b1\u00a00.09,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE\u2010PCOS. We propose that the attenuated ET\u20101\u2010induced vasodilatation in AE\u2010PCOS is a consequence of androgen receptor\u2010mediated, suppressed ET\n                      <jats:sub>B<\/jats:sub>\n                      R\u2010stimulated NO production, and is reversed with EE.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp277756","type":"journal-article","created":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T02:16:25Z","timestamp":1552011385000},"page":"2853-2865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor"],"prefix":"10.1113","volume":"597","author":[{"given":"Charlotte W.","family":"Usselman","sequence":"first","affiliation":[{"name":"John B. Pierce Laboratory Yale School of Medicine  New Haven CT USA"},{"name":"Department of Obstetrics Gynecology and Reproductive Sciences Yale School of Medicine  New Haven CT USA"},{"name":"Department of Kinesiology and Physical Education McGill University  Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timur O.","family":"Yarovinsky","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Cardiovascular Medicine) and Immunobiology Yale School of Medicine  New Haven CT USA"},{"name":"Yale Cardiovascular Research Center Yale University School of Medicine  New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances E.","family":"Steele","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Cardiovascular Medicine) and Immunobiology Yale School of Medicine  New Haven CT USA"},{"name":"Yale Cardiovascular Research Center Yale University School of Medicine  New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl A.","family":"Leone","sequence":"additional","affiliation":[{"name":"John B. Pierce Laboratory Yale School of Medicine  New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh S.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Obstetrics Gynecology and Reproductive Sciences Yale School of Medicine  New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Bender","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (Cardiovascular Medicine) and Immunobiology Yale School of Medicine  New Haven CT USA"},{"name":"Yale Cardiovascular Research Center Yale University School of Medicine  New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-5031","authenticated-orcid":false,"given":"Nina S.","family":"Stachenfeld","sequence":"additional","affiliation":[{"name":"John B. Pierce Laboratory Yale School of Medicine  New Haven CT USA"},{"name":"Department of Obstetrics Gynecology and Reproductive Sciences Yale School of Medicine  New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,27]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/348730a0"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-S014"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3948"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2008.06.035"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-10-0709"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0188-4409(01)00325-3"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1000485"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00397.2010"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01354.2011"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0410"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00681.2014"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.24.9797"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399408000598"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.10.7904"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704198"},{"key":"e_1_2_5_17_1","first-page":"511","article-title":"Gender differences in the expression of endothelin receptors in human saphenous veins in vitro","volume":"285","author":"Ergul A","year":"1998","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2006.00569.x"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.287.3.356"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0801994"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.217"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.91508.2008"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.080952"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00858.2007"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1159"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.8.2863"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.11.4892"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2014.102"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-1233"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.91.5.2407"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.583450"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0151"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1159\/000484107"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108263"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.8.3185"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.17.2317"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.22.9.1462"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000153"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2014.04.004"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.10.1410"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2015-1161"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex308"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1097\/GRF.0b013e31802f351b"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2003.01842.x"},{"key":"e_1_2_5_45_1","doi-asserted-by":"crossref","first-page":"21778","DOI":"10.1016\/S0021-9258(17)31872-0","article-title":"Molecular and functional characterization of the non\u2010isopeptide\u2010selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase","volume":"269","author":"Tsukahara H","year":"1994","journal-title":"J Biol Chem"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-08-1169"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00598.2005"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00399.2005"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.8.752"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.216218"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00343.2013"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00780.2011"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/332411a0"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.3906\/sag-1401-4"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01170.2003"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP277756","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP277756","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP277756","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP277756","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T12:42:53Z","timestamp":1694176973000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP277756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,27]]},"references-count":54,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2019,6]]}},"alternative-id":["10.1113\/JP277756"],"URL":"https:\/\/doi.org\/10.1113\/jp277756","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,27]]},"assertion":[{"value":"2019-01-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}