Sex differences in progesterone-induced relaxation in the coronary bed from normotensive rats

in Journal of Molecular Endocrinology
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  • 1 Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Espirito Santo, Brazil
  • 2 Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Correspondence should be addressed to R L dos Santos: rogerlyrio@hotmail.com
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Progesterone seems to play a role in cardiovascular physiology since its receptors are expressed on endothelial cells from both sexes of mammals. However, little is known about its role on the coronary circulation. Thus, this study aims to evaluate the effect of acute administration of progesterone on the coronary bed and the endothelial pathways involved in this action in normotensive rats of both sexes. A dose–response curve of progesterone (1–50 μmol/L) in isolated hearts using the Langendorff preparation was performed. Baseline coronary perfusion pressure (CPP) was determined, and the vasoactive effect of progesterone was evaluated before and after infusion with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin, catalase, and Tiron. The analysis of nitric oxide (NO) and superoxide anion (O2 · ) was performed by DAF-2DA and DHE, respectively. Female group showed higher CPP. Nevertheless, progesterone promoted a similar relaxing response in both sexes. The use of L-NAME increased vasodilatory response in both sexes. When indomethacin was used, only the males showed a reduced relaxing response, and in the combined inhibition with L-NAME, indomethacin, and catalase, or with the use of Tiron, only the females presented reduced responses. NO and O2 ·− production has increased in female group, while the male group has increased only NO production. Our results suggest that progesterone is able to modulate vascular reactivity in coronary vascular bed with a vasodilatory response in both sexes. These effects seem to be, at least in part, mediated by different endothelial pathways, involving NO and EDH pathways in females and NO and prostanoids pathways in males.

 

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  • Barbagallo M, Dominguez LJ, Licata G, Shan J, Bing L, Karpinski E, Pang PKT & Resnick LM 2001 Vascular effects of progesterone: role of cellular calcium regulation. Hypertension 142147. (https://doi.org/10.1161/01.HYP.37.1.142)

    • Search Google Scholar
    • Export Citation
  • Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, 2018 Heart disease and stroke statistics – 2018 update: a report from the American Heart Association. Circulation e67e492. (https://doi.org/10.1161/CIR.0000000000000558)

    • Search Google Scholar
    • Export Citation
  • Berger V, Beier S, Elger W, Müller U & Stock G 1992 Influence of different progestogens on blood pressure of non-anaesthetized male spontaneously hypertensive rats. Contraception 8397. (https://doi.org/10.1016/0010-7824(92)90134-F)

    • Search Google Scholar
    • Export Citation
  • Cairrão E, Alvarez E, Carvas JM, Santos-Silva AJ & Verde I 2012 Non-genomic vasorelaxant effects of 17β-estradiol and progesterone in rat aorta are mediated by L-type Ca2+ current inhibition. Acta Pharmacologica Sinica 615624. (https://doi.org/10.1038/aps.2012.4)

    • Search Google Scholar
    • Export Citation
  • Campbell WB & Harder DR 2001 Prologue: EDHF–what is it? American Journal of Physiology: Heart and Circulatory Physiology H2413H2416. (https://doi.org/10.1152/ajpheart.2001.280.6.H2413)

    • Search Google Scholar
    • Export Citation
  • CONCEA MCT 2016 Normativas Do CONCEA Para Produção, Manutenção de Animais Em Atividades de Ensino Ou Pesquisa Científica: Lei, Decreto, Portarias, Resoluções, Normativas e Orientações Técnicas. Brasília.

    • Search Google Scholar
    • Export Citation
  • Crews JK & Khalil RA 1999 Antagonistic effects of 17-estradiol, progesterone, and testosterone on Ca 2 entry mechanisms of coronary vasoconstriction. Arteriosclerosis, Thrombosis, and Vascular Biology 10341040. (https://doi.org/10.1161/01.ATV.19.4.1034)

    • Search Google Scholar
    • Export Citation
  • Cutini P, Sellés J & Massheimer V 2009 Cross-talk between rapid and long term effects of progesterone on vascular tissue. Journal of Steroid Biochemistry and Molecular Biology 3643. (https://doi.org/10.1016/j.jsbmb.2009.02.014)

    • Search Google Scholar
    • Export Citation
  • Cutini PH, Campelo AE & Massheimer VL 2014 Differential regulation of endothelium behavior by progesterone and medroxyprogesterone acetate. Journal of Endocrinology 179193. (https://doi.org/10.1530/JOE-13-0263)

    • Search Google Scholar
    • Export Citation
  • Debortoli AR, Rouver WDN, Delgado NTB, Mengal V, Claudio ERG, Pernomian L, Bendhack LM, Moysés MR & Santos RLD 2017 GPER modulates tone and coronary vascular reactivity in male and female rats. Journal of Molecular Endocrinology 171180. (https://doi.org/10.1530/JME-16-0117)

    • Search Google Scholar
    • Export Citation
  • Faraci FM & Didion SP 2004 Vascular protection: superoxide dismutase isoforms in the vessel wall. Arteriosclerosis, Thrombosis, and Vascular Biology 13671373. (https://doi.org/10.1161/01.ATV.0000133604.20182.cf)

    • Search Google Scholar
    • Export Citation
  • Figueroa-Valverde LF, Cedillo FD, Ramos ML, Cervera EG, Quijano K & Cordoba J 2011 Changes induced by estradiol-ethylenediamine derivative on perfusion pressure and coronary resistance in isolated rat heart: L-type calcium channel. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 2732. (https://doi.org/10.5507/bp.2011.018)

    • Search Google Scholar
    • Export Citation
  • Gluais P, Edwards G, Weston AH, Vanhoutte PM & Félétou M 2005 Hydrogen peroxide and endothelium-dependent hyperpolarization in the guinea-pig carotid artery. European Journal of Pharmacology 219224. (https://doi.org/10.1016/j.ejphar.2005.02.042)

    • Search Google Scholar
    • Export Citation
  • Goldman JM, Murr AS & Cooper RL 2007 The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Research: Part B, Developmental and Reproductive Toxicology 8497. (https://doi.org/10.1002/bdrb.20106)

    • Search Google Scholar
    • Export Citation
  • Hadi HAR, Carr CS & Al Suwaidi J 2005 Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vascular Health and Risk Management 183198.

    • Search Google Scholar
    • Export Citation
  • Ingegno MD, Money SR, Thelmo W, Greene GL, Davidian M, Jaffe BM & Pertschuk LP 1988 Progesterone receptors in the human heart and great vessels. Laboratory Investigation 353356.

    • Search Google Scholar
    • Export Citation
  • Kaur S, Benton WL, Tongkhuya SA, Lopez CMC, Uphouse L & Averitt DL 2018 Sex Differences and Estrous Cycle Effects of Peripheral Serotonin-Evoked Rodent Pain Behaviors. Neuroscience 384 87100. (https://doi.org/10.1016/j.neuroscience.2018.05.017)

    • Search Google Scholar
    • Export Citation
  • Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF & Hamilton CA 1999 Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. Hypertension 13531358. (https://doi.org/10.1161/01.HYP.33.6.1353)

    • Search Google Scholar
    • Export Citation
  • Knock GA, Snetkov VA, Shaifta Y, Connolly M, Drndarski S, Noah A, Pourmahram GE, Becker S, Aaronson PI & Ward JPT 2009 Superoxide constricts rat pulmonary arteries via Rho-kinase-mediated Ca2+ sensitization. Free Radical Biology and Medicine 633642. (https://doi.org/10.1016/J.FREERADBIOMED.2008.11.015)

    • Search Google Scholar
    • Export Citation
  • Laursen JB, Somers M, Kurz S, Mccann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T & Harrison DG 2001 Endothelial regulation of vasomotion in ApoE-deficient mice implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 12821288. (https://doi.org/10.1161/01.CIR.103.9.1282)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Terata K, Chai Q, Li H, Kleinman LH & Gutterman DD 2002 Peroxynitrite inhibits Ca2+-activated K+ channel activity in smooth muscle of human coronary arterioles. Circulation Research 10701076. (https://doi.org/10.1161/01.RES.0000046003.14031.98)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC & Gutterman DD 2003 Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circulation Research 573580. (https://doi.org/10.1161/01.RES.0000091261.19387.AE)

    • Search Google Scholar
    • Export Citation
  • Lucchesi PA, Belmadani S & Matrougui K 2005 Hydrogen peroxide acts as both vasodilator and vasoconstrictor in the control of perfused mouse mesenteric resistance arteries. Journal of Hypertension 571579. (https://doi.org/10.1097/01.hjh.0000160214.40855.79)

    • Search Google Scholar
    • Export Citation
  • Marcondes FK, Bianchi FJ & Tanno AP 2002 Determination of the estrous cycle phases of rats: some helpful considerations. Brazilian Journal of Biology 609614. (https://doi.org/10.1590/S1519-69842002000400008)

    • Search Google Scholar
    • Export Citation
  • Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H & Takeshita A 2000 Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. Journal of Clinical Investigation 15211530. (https://doi.org/10.1172/JCI10506)

    • Search Google Scholar
    • Export Citation
  • Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kunihiro I, Mukai Y, Hirakawa Y & Takeshita A 2002 Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. Biochemical and Biophysical Research Communications 909913. (https://doi.org/10.1006/BBRC.2001.6278)

    • Search Google Scholar
    • Export Citation
  • Matoba T, Shimokawa H, Morikawa K, Kubota H, Kunihiro I, Urakami-Harasawa L, Mukai Y, Hirakawa Y, Akaike T & Takeshita A 2003 Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels. Arteriosclerosis, Thrombosis, and Vascular Biology 12241230. (https://doi.org/10.1161/01.ATV.0000078601.79536.6C)

    • Search Google Scholar
    • Export Citation
  • Mcculloch AI & Randall MD 1998 Sex diferences in the relative contributions of nitric oxide and EDHF to agonist-stimulated endothelium-dependent relaxations in the rat isolated mesenteric arterial bed. British Journal of Pharmacology 17001706. (https://doi.org/10.1038/sj.bjp.0701781)

    • Search Google Scholar
    • Export Citation
  • Mendelsohn ME & Karas RH 2005 Molecular and cellular basis of cardiovascular gender differences. Science 15831587. (https://doi.org/10.1126/science.1112062)

    • Search Google Scholar
    • Export Citation
  • Minshall RD, Pavcnik D, Browne DL & Hermsmeyer K 2002 Nongenomic vasodilator action of progesterone on primate coronary arteries. Journal of Applied Physiology 701708. (https://doi.org/10.1152/japplphysiol.00689.2001)

    • Search Google Scholar
    • Export Citation
  • Molinari C, Battaglia A, Grossini E, Mary DASG, Stoker JB, Surico N & Vacca G 2001 The effect of progesterone on coronary blood flow in anaesthetized pigs. Experimental Physiology 101108. (https://doi.org/10.1113/eph8602076)

    • Search Google Scholar
    • Export Citation
  • Morel Y, Roucher F, Plotton I, Goursaud C, Tardy V & Mallet D 2016 Evolution of steroids during pregnancy: maternal, placental and fetal synthesis. Annales d’Endocrinologie 8289. (https://doi.org/10.1016/J.ANDO.2016.04.023)

    • Search Google Scholar
    • Export Citation
  • Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder MAH, Hatanaka M, Fujiki T, Maeda H, Takahashi S, 2003 Pivotal role of Cu,Zn-superoxide dismutase in endothelium dependent hyperpolarization. Journal of Clinical Investigation 18711879. (https://doi.org/10.1172/JCI19351)

    • Search Google Scholar
    • Export Citation
  • Moysés MR, Barker LA & Cabral AM 2001 Sex hormone modulation of serotonin-induced coronary vasodilation in isolated heart. Brazilian Journal of Medical and Biological Research 949958. (https://doi.org/10.1590/S0100-879X2001000700014)

    • Search Google Scholar
    • Export Citation
  • Murphy JG & Khalil RA 1999 Decreased [Ca(2+)](i) during inhibition of coronary smooth muscle contraction by 17beta-estradiol, progesterone, and testosterone. Journal of Pharmacology and Experimental Therapeutics 4452.

    • Search Google Scholar
    • Export Citation
  • Nakano Y, Oshima T, Matsuura H, Kajiyama G & Kambe M 1998 Effect of 17β-estradiol on inhibition of platelet aggregation in vitro is mediated by an increase in NO synthesis. Arteriosclerosis, Thrombosis, and Vascular Biology 961967. (https://doi.org/10.1161/01.ATV.18.6.961)

    • Search Google Scholar
    • Export Citation
  • Orshal JM & Khalil RA 2004 Gender, sex hormones, and vascular tone. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology R233R249. (https://doi.org/10.1152/ajpregu.00338.2003)

    • Search Google Scholar
    • Export Citation
  • Pang Y, Dong J & Thomas P 2015 Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α. American Journal of Physiology: Endocrinology and Metabolism E899E911. (https://doi.org/10.1152/ajpendo.00527.2014)

    • Search Google Scholar
    • Export Citation
  • Ramírez-Rosas MB, Cobos-Puc LE, Sánchez-López A, Gutiérrez-Lara EJ & Centurión D 2014 Pharmacological characterization of the mechanisms involved in the vasorelaxation induced by progesterone and 17β-estradiol on isolated canine basilar and internal carotid arteries. Steroids 3340. (https://doi.org/10.1016/j.steroids.2014.07.010)

    • Search Google Scholar
    • Export Citation
  • Rosano GMC, Spoletini I & Vitale C 2017 Cardiovascular disease in women, is it different to men? The role of sex hormones. Climacteric 125128. (https://doi.org/10.1080/13697137.2017.1291780)

    • Search Google Scholar
    • Export Citation
  • Ross RL, Serock MR & Khalil RA 2008 Experimental benefits of sex hormones on vascular function and the outcome of hormone therapy in cardiovascular disease. Current Cardiology Reviews 309322. (https://doi.org/10.2174/157340308786349462)

    • Search Google Scholar
    • Export Citation
  • Rossetti MF, Cambiasso MJ, Holschbach MA & Cabrera R 2016 Oestrogens and progestagens: synthesis and action in the brain. Journal of Neuroendocrinology 28 111. (https://doi.org/10.1111/jne.12402)

    • Search Google Scholar
    • Export Citation
  • Rouver WN, Delgado NTB, Menezes JB, Santos RL & Moyses MR 2015 Testosterone replacement therapy prevents alterations of coronary vascular reactivity caused by hormone deficiency induced by castration. PLoS ONE e0137111. (https://doi.org/10.1371/journal.pone.0137111)

    • Search Google Scholar
    • Export Citation
  • Rupnow HL, Phernetton TM, Shaw CE, Modrick ML, Bird IM & Magness RR 2001 Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS. American Journal of Physiology: Heart and Circulatory Physiology H1699H1705. (https://doi.org/10.1152/ajpheart.2001.280.4.H1699)

    • Search Google Scholar
    • Export Citation
  • Santos RL, Abreu GR, Bissoli NS & Moysés MR 2004 Endothelial mediators of 17β-estradiol-induced coronary vasodilation in the isolated rat heart. Brazilian Journal of Medical and Biological Research 569575. (https://doi.org/10.1590/S0100-879X2004000400014)

    • Search Google Scholar
    • Export Citation
  • Santos RL, Da Silva FB, Ribeiro RF & Stefanon I 2014 Sex hormones in the cardiovascular system. Hormone Molecular Biology and Clinical Investigation 89103. (https://doi.org/10.1515/hmbci-2013-0048)

    • Search Google Scholar
    • Export Citation
  • Santos RL, Lima JT, Rouver WN & Moysés MR 2016 Deficiency of sex hormones does not affect 17-β-estradiol-induced coronary vasodilation in the isolated rat heart. Brazilian Journal of Medical and Biological Research e5058. (https://doi.org/10.1590/1414-431X20165058)

    • Search Google Scholar
    • Export Citation
  • Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N, Sasaki T, Tsujioka K, Makino H & Kashihara N 2005 NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. American Journal of Physiology: Renal Physiology F1144F1152. (https://doi.org/10.1152/ajprenal.00221.2004)

    • Search Google Scholar
    • Export Citation
  • Scotland RS, Madhani M, Chauhan S, Moncada S, Andresen J, Nilsson H, Hobbs AJ & Ahluwalia A 2005 Investigation of vascular responses in endothelial nitric oxide synthase/cyclooxygenase-1 double-knockout mice key role for endothelium-derived hyperpolarizing factor in the regulation of blood pressure in vivo. Circulation 796803. (https://doi.org/10.1161/01.CIR.0000155238.70797.4E)

    • Search Google Scholar
    • Export Citation
  • Selles J, Polini N, Alvarez C & Massheimer V 2001 Progesterone and 17-estradiol acutely stimulate nitric oxide synthase activity in rat aorta and inhibit platelet aggregation. Life Sciences 815827. (https://doi.org/10.1016/S0024-3205(01)01174-2)

    • Search Google Scholar
    • Export Citation
  • Selles J, Polini N, Alvarez C & Massheimer V 2002 Nongenomic action of progesterone in rat aorta: role of nitric oxide and prostaglandins. Cellular Signalling 431436. (https://doi.org/10.1016/S0898-6568(01)00265-0)

    • Search Google Scholar
    • Export Citation
  • Shimokawa H & Godo S 2016 Diverse functions of endothelial NO synthases system: NO and EDH. Journal of Cardiovascular Pharmacology 361366. (https://doi.org/10.1097/FJC.0000000000000348)

    • Search Google Scholar
    • Export Citation
  • Silva JF, Capettini LSA, da Silva JFP, Sales-Junior P, Cruz JS, Cortes SF & Lemos VS 2016 Mechanisms of vascular dysfunction in acute phase of Trypanosoma cruzi infection in mice. Vascular Pharmacology 7381. (https://doi.org/10.1016/J.VPH.2016.03.002)

    • Search Google Scholar
    • Export Citation
  • Simoncini T, Mannella P, Fornari L, Caruso A, Willis MY, Garibaldi S, Baldacci C & Genazzani AR 2004 Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells. Endocrinology 57455756. (https://doi.org/10.1210/en.2004-0510)

    • Search Google Scholar
    • Export Citation
  • Simoncini T, Fu XD, Caruso A, Garibaldi S, Baldacci C, Giretti MS, Mannella P, Flamini MI, Sanchez AM & Genazzani AR 2007 Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors. Human Reproduction 23252334. (https://doi.org/10.1093/humrep/dem109)

    • Search Google Scholar
    • Export Citation
  • Stuehr D, Pou S & Rosen GM 2001 Oxygen reduction by nitric-oxide synthases. Journal of Biological Chemistry 1453314536. (https://doi.org/10.1074/jbc.R100011200)

    • Search Google Scholar
    • Export Citation
  • Tang EHC & Vanhoutte PM 2009 Prostanoids and reactive oxygen species: team players in endothelium-dependent contractions. Pharmacology and Therapeutics 140149. (https://doi.org/10.1016/J.PHARMTHERA.2009.02.006)

    • Search Google Scholar
    • Export Citation
  • Tarafdar A & Pula G 2018 The role of NADPH oxidases and oxidative stress in neurodegenerative disorders. International Journal of Molecular Sciences 3824. (https://doi.org/10.3390/ijms19123824)

    • Search Google Scholar
    • Export Citation
  • Thompson J & Khalil RA 2003 Gender differences in the regulation of vascular tone. Clinical and Experimental Pharmacology and Physiology 115. (https://doi.org/10.1046/j.1440-1681.2003.03790.x)

    • Search Google Scholar
    • Export Citation
  • Vázquez F, Rodríguez-Manzaneque JC, Lydon JP, Edwards DP, O’Malley BW & Iruela-Arispe ML 1999 Progesterone regulates proliferation of endothelial cells. Journal of Biological Chemistry 21852192. (https://doi.org/10.1074/jbc.274.4.2185)

    • Search Google Scholar
    • Export Citation
  • Wassmann K, Wassmann S & Nickenig G 2005 Progesterone antagonizes the vasoprotective effect of estrogen on antioxidant enzyme expression and function. Circulation Research 10461054. (https://doi.org/10.1161/01.RES.0000188212.57180.55)

    • Search Google Scholar
    • Export Citation
  • Wheal AJ, Alexander SPH & Randall MD 2012 Hydrogen peroxide as a mediator of vasorelaxation evoked by N-oleoylethanolamine and anandamide in rat small mesenteric arteries. European Journal of Pharmacology 384390. (https://doi.org/10.1016/J.EJPHAR.2011.11.033)

    • Search Google Scholar
    • Export Citation
  • Xiu F, Anipindi VC, Nguyen PV, Boudreau J, Liang H, Wan Y, Snider DP & Kaushic C 2016 High physiological concentrations of progesterone reverse estradiol-mediated changes in differentiation and functions of bone marrow derived dendritic cells. PLoS ONE e0153304. (https://doi.org/10.1371/journal.pone.0153304)

    • Search Google Scholar
    • Export Citation
  • Zou MH & Ullrich V 1996 Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Letters 101104. (https://doi.org/10.1016/0014-5793(96)00160-3)

    • Search Google Scholar
    • Export Citation
  • Zou MH, Shi C & Cohen RA 2002 Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. Journal of Clinical Investigation 817826. (https://doi.org/10.1172/JCI14442)

    • Search Google Scholar
    • Export Citation