Margaret A Zimmerman1, Dillion D Hutson1, Franck Mauvais-Jarvis2, Sarah H Lindsey1. 1. Department of Pharmacology, Section of Endocrinology, Tulane University School of Medicine, New Orleans, LA. 2. Department of Medicine, Section of Endocrinology, Tulane University School of Medicine, New Orleans, LA.
Abstract
OBJECTIVE: A new strategy for menopausal hormone therapy replaces medroxyprogesterone with the selective estrogen receptor modulator bazedoxifene. While the agonist or antagonist activity of bazedoxifene has been examined in other tissues, the current study explored the impact of bazedoxifene on resistance artery reactivity. We hypothesized that bazedoxifene may induce greater vasoprotective effects than estradiol due to enhanced activation of the G-protein-coupled estrogen receptor. METHODS: We measured the vasodilation of mesenteric resistance arteries from adult male and female wild-type and G-protein-coupled estrogen receptor knockout mice (n = 58) in response to increasing concentrations of bazedoxifene, medroxyprogesterone, and estradiol, and also the impact of these compounds on the responses to phenylephrine and sodium nitroprusside. RESULTS: Bazedoxifene-induced vasorelaxation was greater than estradiol and blunted phenylephrine-induced contraction-an effect not observed with estradiol. Neither estradiol nor bazedoxifene altered relaxation to sodium nitroprusside. The combination of bazedoxifene + estradiol promoted greater vasodilation than medroxyprogesterone + estradiol, and opposed phenylephrine-induced contraction, whereas medroxyprogesterone + estradiol failed to attenuate this response. Both bazedoxifene + estradiol and medroxyprogesterone + estradiol enhanced sodium nitroprusside-induced relaxation in females. Vascular responses were similar in both sexes in wild-type and G-protein-coupled estrogen receptor knockout mice. CONCLUSION: Bazedoxifene and bazedoxifene + estradiol relaxed mesenteric arteries and opposed vasoconstriction to a greater degree than estradiol or medroxyprogesterone + estradiol. These effects were independent of sex and G-protein-coupled estrogen receptor expression. We conclude that bazedoxifene may provide vascular benefits over estrogen alone or estrogen plus progestogen combinations in postmenopausal women.
OBJECTIVE: A new strategy for menopausal hormone therapy replaces medroxyprogesterone with the selective estrogen receptor modulator bazedoxifene. While the agonist or antagonist activity of bazedoxifene has been examined in other tissues, the current study explored the impact of bazedoxifene on resistance artery reactivity. We hypothesized that bazedoxifene may induce greater vasoprotective effects than estradiol due to enhanced activation of the G-protein-coupled estrogen receptor. METHODS: We measured the vasodilation of mesenteric resistance arteries from adult male and female wild-type and G-protein-coupled estrogen receptor knockout mice (n = 58) in response to increasing concentrations of bazedoxifene, medroxyprogesterone, and estradiol, and also the impact of these compounds on the responses to phenylephrine and sodium nitroprusside. RESULTS:Bazedoxifene-induced vasorelaxation was greater than estradiol and blunted phenylephrine-induced contraction-an effect not observed with estradiol. Neither estradiol nor bazedoxifene altered relaxation to sodium nitroprusside. The combination of bazedoxifene + estradiol promoted greater vasodilation than medroxyprogesterone + estradiol, and opposed phenylephrine-induced contraction, whereas medroxyprogesterone + estradiol failed to attenuate this response. Both bazedoxifene + estradiol and medroxyprogesterone + estradiol enhanced sodium nitroprusside-induced relaxation in females. Vascular responses were similar in both sexes in wild-type and G-protein-coupled estrogen receptor knockout mice. CONCLUSION:Bazedoxifene and bazedoxifene + estradiol relaxed mesenteric arteries and opposed vasoconstriction to a greater degree than estradiol or medroxyprogesterone + estradiol. These effects were independent of sex and G-protein-coupled estrogen receptor expression. We conclude that bazedoxifene may provide vascular benefits over estrogen alone or estrogen plus progestogen combinations in postmenopausal women.
Authors: C P Miller; M D Collini; B D Tran; H A Harris; Y P Kharode; J T Marzolf; R A Moran; R A Henderson; R H Bender; R J Unwalla; L M Greenberger; J P Yardley; M A Abou-Gharbia; C R Lyttle; B S Komm Journal: J Med Chem Date: 2001-05-24 Impact factor: 7.446
Authors: Jennifer A Miner; Emily R Martini; Michael M Smith; Vienna E Brunt; Paul F Kaplan; John R Halliwill; Christopher T Minson Journal: Am J Physiol Heart Circ Physiol Date: 2011-08-19 Impact factor: 4.733
Authors: Elizabeth Barrett-Connor; Lori Mosca; Peter Collins; Mary Jane Geiger; Deborah Grady; Marcel Kornitzer; Michelle A McNabb; Nanette K Wenger Journal: N Engl J Med Date: 2006-07-13 Impact factor: 91.245
Authors: Liu Liu; Shreya Kashyap; Brennah Murphy; Dillion D Hutson; Rebecca A Budish; Emma H Trimmer; Margaret A Zimmerman; Aaron J Trask; Kristin S Miller; Mark C Chappell; Sarah H Lindsey Journal: Am J Physiol Heart Circ Physiol Date: 2016-02-12 Impact factor: 4.733
Authors: María Castelló-Ruiz; Juan B Salom; Ricardo Fernández-Musoles; María C Burguete; Mikahela A López-Morales; Alessandro Arduini; Teresa Jover-Mengual; David Hervás; Germán Torregrosa; Enrique Alborch Journal: J Cardiovasc Pharmacol Date: 2016-10 Impact factor: 3.105
Authors: Stuart L Silverman; Claus Christiansen; Harry K Genant; Slobodan Vukicevic; José R Zanchetta; Tobie J de Villiers; Ginger D Constantine; Arkadi A Chines Journal: J Bone Miner Res Date: 2008-12 Impact factor: 6.741
Authors: JoAnn E Manson; Rowan T Chlebowski; Marcia L Stefanick; Aaron K Aragaki; Jacques E Rossouw; Ross L Prentice; Garnet Anderson; Barbara V Howard; Cynthia A Thomson; Andrea Z LaCroix; Jean Wactawski-Wende; Rebecca D Jackson; Marian Limacher; Karen L Margolis; Sylvia Wassertheil-Smoller; Shirley A Beresford; Jane A Cauley; Charles B Eaton; Margery Gass; Judith Hsia; Karen C Johnson; Charles Kooperberg; Lewis H Kuller; Cora E Lewis; Simin Liu; Lisa W Martin; Judith K Ockene; Mary Jo O'Sullivan; Lynda H Powell; Michael S Simon; Linda Van Horn; Mara Z Vitolins; Robert B Wallace Journal: JAMA Date: 2013-10-02 Impact factor: 56.272
Authors: Benard O Ogola; Caleb M Abshire; Bruna Visniauskas; Jasmine X Kiley; Alec C Horton; Gabrielle L Clark-Patterson; Isabella Kilanowski-Doroh; Zaidmara Diaz; Anne N Bicego; Alexandra B McNally; Margaret A Zimmerman; Leanne Groban; Aaron J Trask; Kristin S Miller; Sarah H Lindsey Journal: Am J Physiol Heart Circ Physiol Date: 2022-06-24 Impact factor: 5.125
Authors: Margaret A Zimmerman; Benard O Ogola; Mary M Wilkinson; Bruna Visniauskas; Carmen De Miguel; Jill M Daniel; Sarah H Lindsey Journal: Menopause Date: 2020-12 Impact factor: 3.310
Authors: Benard O Ogola; Margaret A Zimmerman; Venkata N Sure; Kaylee M Gentry; Jennifer L Duong; Gabrielle L Clark; Kristin S Miller; Prasad V G Katakam; Sarah H Lindsey Journal: Front Endocrinol (Lausanne) Date: 2019-08-27 Impact factor: 5.555