Progesterone modulates endothelium-dependent coronary vascular reactivity in SHR

in Journal of Molecular Endocrinology
View More View Less
  • 1 Department of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, Espirito Santo, Brazil

Correspondence should be addressed to R L dos Santos: rogerlyrio@hotmail.com

Although progesterone has the ability to promote dilation of vascular smooth muscle, its role in coronary circulation is still poorly characterized, especially in essential hypertension and in a model of endogenous deficiency of ovarian hormones. Thus, this study evaluated the effect of progesterone treatment on endothelium-dependent coronary vascular reactivity in hypertensive (SHR) and ovariectomized rats. Adult SHR aged 8–10 weeks were divided into: SHAM, Ovariectomized (OVX) and Ovariectomized + treatment with 2 mg/kg/day of progesterone for 15 days (OVX-P4). Coronary vascular reactivity was investigated using the modified Langendorff method. After stabilization, baseline coronary perfusion pressure (CPP) was recorded and vascular reactivity to bradykinin (BK, 0.1–1000 ng) were assessed before and after infusion, either individually or in combination, with Nω-nitro-l-arginine methyl ester (l-NAME), indomethacin or clotrimazole. Scanning electron microscopy was used for qualitative analysis of the endothelium. OVX and OVX-P4 groups had a higher baseline CPP compared to that of the SHAM group. BK was able to promote vasodilation in all groups. However, relaxation to BK was less pronounced in the OVX group when compared to SHAM, with architecture loss and areas of cell atrophy having been observed. Progesterone treatment prevented this injury. Perfusion with l-NAME induced greater damage to the SHAM group, while the use of indomethacin led to a significant reduction in the vasodilator response to BK in the OVX-P4 group. Taken together, our results show that progesterone modulates endothelium-dependent coronary vasodilation in SHR ovariectomized, preventing damage caused by ovarian hormonal deficiency through a mechanism that involves prostanoid pathway.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 265 265 43
Full Text Views 13 13 2
PDF Downloads 14 14 4
  • Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Preto H, Bonds D, Brunner R, Brzyski R & Caan B et al.2004 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291 17011712. (https://doi.org/10.1001/jama.291.14.1701)

    • Search Google Scholar
    • Export Citation
  • Baldo MP, Forechi L, Morra EAS, Zaniqueli D, Machado RC, Lunz W, Rodrigues SL & Mill JG 2011 Long-term use of low-dose spironolactone in spontaneously hypertensive rats : effects on left ventricular hypertrophy and stiffness. Pharmacological Reports 63 975982. (https://doi.org/10.1016/s1734-1140(1170613-2)

    • Search Google Scholar
    • Export Citation
  • Bernardi F, Pluchino N, Pieri M, Begliuomini S, Lenzi E, Puccetti S, Casarosa E, Luisi M & Genazzani AR 2006 Progesterone and medroxyprogesterone acetate effects on central and peripheral allopregnanolone and beta-endorphin levels. Neuroendocrinology 83 348359. (https://doi.org/10.1159/000095400)

    • Search Google Scholar
    • Export Citation
  • Borgo MV, Claudio ERG, Silva FB, Romero WG, Gouvea SA, Moysés MR, Santos RL, Almeida SA, Podratz PL & Graceli JB et al.2016 Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats. Brazilian Journal of Medical and Biological Research 49 e4655. (https://doi.org/10.1590/1414-431X20154655)

    • Search Google Scholar
    • Export Citation
  • Chataigneau T, Zerr M, Chataigneau M, Hudlett F, Hirn C, Pernot F & Schini-Kerth VB 2004 Chronic treatment with progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats. Menopause 11 255263. (https://doi.org/10.1097/01.GME.0000097847.95550.E3)

    • Search Google Scholar
    • Export Citation
  • Cheng TL, Lin YY, Su CT, Hu CC & Yang AL 2016 Improvement of acetylcholine-induced vasodilation by acute exercise in ovariectomized hypertensive rats. Chinese Journal of Physiology 59 165172. (https://doi.org/10.4077/CJP.2016.BAE387)

    • Search Google Scholar
    • Export Citation
  • Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA & Fitzgerald GA 2002 Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296 539541. (https://doi.org/10.1126/science.1068711)

    • Search Google Scholar
    • Export Citation
  • Chu LY, Liou JY & Wu KK 2015 Prostacyclin protects vascular integrity via PPAR/14-3-3 pathway. Prostaglandins and Other Lipid Mediators 118–119 1927. (https://doi.org/10.1016/j.prostaglandins.2015.04.006)

    • Search Google Scholar
    • Export Citation
  • Claudio ERG, Endlich PW, Santos RL, Moysés MR, Bissoli NS, Gouvêa SA, Silva JF, Lemos VS & Abreu GR 2014 Effects of chronic swimming training and oestrogen therapy on coronary vascular reactivity and expression of antioxidant enzymes in ovariectomized rats. PLOS ONE 8 e64806. (https://doi.org/10.1371/journal.pone.0064806)

    • Search Google Scholar
    • Export Citation
  • Cox MW, Fu W, Chai H, Paladugu R, Lin PH, Lumsden AB, Yao Q & Chen C 2005 Effects of progesterone and estrogen on endothelial dysfunction in porcine coronary arteries. Journal of Surgical Research 124 104111. (https://doi.org/10.1016/j.jss.2004.09.003)

    • Search Google Scholar
    • Export Citation
  • Cunha TRD, Giesen JAS, Rouver WN, Costa ED, Grando MD, Lemos VS, Bendhack LM & Santos RLD 2020 Effects of progesterone treatment on endothelium-dependent coronary relaxation in ovariectomized rats. Life Sciences 247 117391. (https://doi.org/10.1016/j.lfs.2020.117391)

    • 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 115 3643. (https://doi.org/10.1016/j.jsbmb.2009.02.014)

    • Search Google Scholar
    • Export Citation
  • Cutini PH, Campelo AE, Agriello E, Sandoval MJ, Rauschemberger MB & Massheimer VL 2012 The role of sex steroids on cellular events involved in vascular disease. Journal of Steroid Biochemistry and Molecular Biology 132 322330. (https://doi.org/10.1016/j.jsbmb.2012.08.001)

    • 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 220 179193. (https://doi.org/10.1530/JOE-13-0263)

    • Search Google Scholar
    • Export Citation
  • Dalpiaz PLM, Lamas AZ, Caliman IF, Ribeiro RF, Abreu GR, Moyses MR, Andrade TU, Gouvea SA, Alves MF & Carmona AK et al.2015 Sex hormones promote opposite effects on ACE and ACE2 activity, hypertrophy and cardiac contractility in spontaneously hypertensive rats. PLOS ONE 10 e0127515. (https://doi.org/10.1371/journal.pone.0127515)

    • 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 59 171180. (https://doi.org/10.1530/JME-16-0117)

    • Search Google Scholar
    • Export Citation
  • Félétou M & Vanhoutte PM 1988 Endothelium-dependent hyperpolarization of canine coronary smooth muscle. British Journal of Pharmacology 93 515524. (https://doi.org/10.1111/j.1476-5381.1988.tb10306.x)

    • Search Google Scholar
    • Export Citation
  • Félétou M & Vanhoutte PM 2006a Endothelial dysfunction: a multifaceted disorder (the Wiggers Award Lecture). American Journal of Physiology. Heart and Circulatory Physiology 291 H985H1002. (https://doi.org/10.1152/ajpheart.00292.2006)

    • Search Google Scholar
    • Export Citation
  • Félétou M & Vanhoutte PM 2006b Endothelium-derived hyperpolarizing factor: where are we now? Arteriosclerosis, Thrombosis, and Vascular Biology 26 12151225. (https://doi.org/10.1161/01.ATV.0000217611.81085.c5)

    • Search Google Scholar
    • Export Citation
  • Garg D, Man Ng SSM, Baig KM, Driggers P & Segars J 2017 Progesterone-mediated non-classical signaling. Trends in Endocrinology and Metabolism 28 656668. (https://doi.org/10.1016/j.tem.2017.05.006)

    • Search Google Scholar
    • Export Citation
  • Giesen JAS, Rouver WDN, Costa ED, Lemos VS & Santos RL 2020 Sex differences in progesterone-induced relaxation in the coronary bed from normotensive rats. Journal of Molecular Endocrinology 64 91102. (doi:10.1530/JME-19-0171)

    • Search Google Scholar
    • Export Citation
  • Henderson KM, Willcox DL & Bruce NW 1983 Effect of infusion of PGI-2, 6-keto-PGF-1α and PGF-2α on luteal function in the pregnant rat. Journal of Reproduction and Fertility 69 1116. (https://doi.org/10.1530/jrf.0.0690011)

    • Search Google Scholar
    • Export Citation
  • Hermenegildo C, Oviedo PJ, García-Martínez MC, García-Pérez MA, Tarín JJ & Cano A 2005 Progestogens stimulate prostacyclin production by human endothelial cells. Human Reproduction 20 15541561. (https://doi.org/10.1093/humrep/deh803)

    • Search Google Scholar
    • Export Citation
  • Ignarro LJ, Buga GM, Wood KS, Byrns RE & Chaudhuri G 1987 Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proceedings of the National Academy of Sciences of the United States of America 84 92659269. (https://doi.org/10.1073/pnas.84.24.9265)

    • Search Google Scholar
    • Export Citation
  • Jacobsen BM & Horwitz KB 2012 Progesterone receptors, their isoforms and progesterone regulated transcription. Molecular and Cellular Endocrinology 357 1829. (https://doi.org/10.1016/j.mce.2011.09.016)

    • Search Google Scholar
    • Export Citation
  • Kang KT 2014 Endothelium-derived relaxing factors of small resistance arteries in hypertension. Toxicological Research 30 141148. (https://doi.org/10.5487/TR.2014.30.3.141)

    • Search Google Scholar
    • Export Citation
  • Kelm M, Feelisch M, Krebber T, Motz W & Strauer BE 1992 The role of nitric oxide in the regulation of coronary vascular resistance in arterial hypertension: comparison of normotensive and spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology 20(Supplement 12) S183S186. (https://doi.org/10.1097/00005344-199204002-00051)

    • Search Google Scholar
    • Export Citation
  • Makila UM, Wahlberg L, Viinikka L & Ylikorkala O 1982 Regulation of prostacyclin and thromboxane production by human umbilical vessels: the effect estradiol and progesterone in a superfusion model. Prostaglandins, Leukotrienes, and Medicine 8 115124. (https://doi.org/10.1016/s0262-1746(8280003-6)

    • Search Google Scholar
    • Export Citation
  • Manson JE, Chlebowski RT, Sthefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA & LaCroix AZ, 2013 The Women’s Health Initiative hormone therapy trials: update and overview of health outcomes during the intervention and post-stopping. JAMA 310 13531368. (https://doi.org/10.1001/jama.2013.278040)

    • 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 = Revista Brasleira de Biologia 62 609614. (https://doi.org/10.1590/s1519-69842002000400008)

    • 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 23 12241230. (https://doi.org/10.1161/01.ATV.0000078601.79536.6C)

    • 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 106 15211530. (https://doi.org/10.1172/JCI10506)

    • Search Google Scholar
    • Export Citation
  • Mendiberri J, Rauschemberger MB, Selles J & Massheimer V 2006 Involvement of phosphoinositide-3-kinase and phospholipase C transduction systems in the non-genomic action of progesterone in vascular tissue. International Journal of Biochemistry & Cell Biology 38 288296. (https://doi.org/10.1016/j.biocel.2005.09.012)

    • Search Google Scholar
    • Export Citation
  • Meyer MR, Fredette NC, Daniel C, Sharma G, Amann K, Arterburn JB, Barton M & Prossnitz ER 2016 Obligatory role for GPER in cardiovascular aging and disease. Science Signaling 9 ra105. (https://doi.org/10.1126/scisignal.aag0240)

    • 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 92 701708. (https://doi.org/10.1152/japplphysiol.00689.2001)

    • Search Google Scholar
    • Export Citation
  • Miura H, Bosnjak JJ, Ning G, Saito T, Miura M & Gutterman DD 2003 Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles. Circulation Research 92 e31e40. (https://doi.org/10.1161/01.RES.0000054200.44505.AB)

    • Search Google Scholar
    • Export Citation
  • Molinari C, Battaglia A, Grossini E, Mary DASG, Stoker JB, Surico N, Vacca G, Fisiologia L, Mediche S & Avogadro OA et al. 2001 The effect of progesterone on coronary blood flow in anaesthetized pigs. Experimental Physiology 86 101108. (https://doi.org/10.1113/eph8602076)

    • Search Google Scholar
    • Export Citation
  • Moncada S, Gryglewski R, Bunting S & Vane JR 1976 An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263 663665. (https://doi.org/10.1038/263663a0)

    • Search Google Scholar
    • Export Citation
  • O’Malley BW & Buller RE 1977 Herman Beerman lecture. Mechanisms of steroid hormone action. Journal of Investigative Dermatology 68 14. (https://doi.org/10.1111/1523-1747.ep12485116)

    • Search Google Scholar
    • Export Citation
  • Oviedo PJ, Sobrino A, Novella S, Rius C, Laguna-Fernandez A, García-Perez MA, Tarín JJ, Cano A & Hermenegildo C 2011 Progestogens reduce thromboxane production by cultured human endothelial cells. Climacteric 14 4148. (https://doi.org/10.3109/13697131003602496)

    • Search Google Scholar
    • Export Citation
  • Palmer RMJ, Ferrige AG & Moncada S 1987 Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327 524526. (https://doi.org/10.1038/327524a0)

    • 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 308 E899E911. (https://doi.org/10.1152/ajpendo.00527.2014)

    • Search Google Scholar
    • Export Citation
  • Pelzer T, Jazbutyte V, Hu K, Segerer S, Nahrendorf M, Nordbeck P, Bonz AW, Muck J, Fritzemeier KH & Hegele-Hartung C et al. 2005 The estrogen receptor-α agonist 16α-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats. Cardiovascular Research 67 604612. (https://doi.org/10.1016/j.cardiores.2005.04.035)

    • Search Google Scholar
    • Export Citation
  • Qiao X, McConnell KR & Khalil RA 2008 Sex steroids and vascular responses in hypertension and aging. Gender Medicine 5(Supplement A) S46S64. (https://doi.org/10.1016/j.genm.2008.03.006)

    • Search Google Scholar
    • Export Citation
  • Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SAA, Howard BV & Johnson KC et al. 2002 Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288 321333. (https://doi.org/10.1001/jama.288.3.321)

    • Search Google Scholar
    • Export Citation
  • Santos RL, Marin EB, Gonçalves WLS, Bissoli NS, Abreu GR & Moysés MR 2010 Sex differences in the coronary vasodilation induced by 17 β-oestradiol in the isolated perfused heart from spontaneously hypertensive rats. Acta Physiologica 200 203210. (https://doi.org/10.1111/j.1748-1716.2010.02140.x)

    • Search Google Scholar
    • Export Citation
  • Schenkel PC, Fernandes RO, Viegas VU, Campos C, Fernandes TRG, Sander AS & Belló-klein A 2014 Catalase influence in the regulation of coronary resistance by estrogen : joint action of nitric oxide and hydrogen peroxide. Oxidative Medicine and Cellular Longevity 2014 6 pages 159852. (https://doi.org/10.1155/2014/159852)

    • 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 69 815827. (https://doi.org/10.1016/S0024-3205(0101174-2)

    • 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 14 431436. (https://doi.org/10.1016/s0898-6568(0100265-0)

    • Search Google Scholar
    • Export Citation
  • Shimokawa H 2020 Reactive oxygen species in cardiovascular health and disease : special references to nitric oxide, hydrogen peroxide, and Rho kinase. Journal of Clinical Biochemistry and Nutrition 66 8391. (https://doi.org/10.3164/jcbn.19-119)

    • Search Google Scholar
    • Export Citation
  • Smith JL, Kupchak BR, Garitaonandia I, Hoang LK, Andrew S, Regalla LM & Lyons TJ 2008 Heterologous expression of human mPRα, mPRβ and mPRγ in yeast confirms their ability to function as membrane progesterone receptors. Steroids 73 11601173. (https://doi.org/10.1016/j.steroids.2008.05.003.Heterologous)

    • Search Google Scholar
    • Export Citation
  • Smyth EM, Grosser T, Wang M, Yu Y & Fitzgerald GA 2009 Prostanoids in health and disease. Journal of Lipid Research 50(Supplement) S423S428. (https://doi.org/10.1194/jlr.R800094-JLR200)

    • Search Google Scholar
    • Export Citation
  • Thomas P 2008 Characteristics of membrane progestin receptor alpha (mPRα) and progesterone membrane receptor component one (PGMRC1) and their roles in mediating rapid progestin actions. Frontiers in Neuroendocrinology 29 292312. (https://doi.org/10.1016/j.yfrne.2008.01.001.Characteristics)

    • Search Google Scholar
    • Export Citation
  • Thomas P & Pang Y 2013 Protective actions of progesterone in the cardiovascular system : potential role of membrane progesterone receptors (mPRs) in mediating rapid effects. Steroids 78 583588. (https://doi.org/10.1016/j.steroids.2013.01.003)

    • Search Google Scholar
    • Export Citation
  • Tsai MJ & Malley BWO 1994 Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annual Review of Biochemistry 63 451486. (https://doi.org/10.1146/annurev.bi.63.070194.002315)

    • Search Google Scholar
    • Export Citation
  • Vanhoutte PM 2009 Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circulation Journal: Official Journal of the Japanese Circulation Society 73 595601. (doi:10.1253/circj.cj-08-1169)

    • 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 274 21852192. (https://doi.org/10.1074/jbc.274.4.2185)

    • Search Google Scholar
    • Export Citation
  • Yada T, Shimokawa H, Hiramatsu O, Kajita T, Shigeto F, Goto M, Ogasawara Y & Kajiya F 2003 Hydrogen peroxide, an endogenous endothelium-derived hyperpolarizing factor, plays an important role in coronary autoregulation in vivo. Circulation 107 10401045. (https://doi.org/10.1161/01.CIR.0000050145.25589.65)

    • Search Google Scholar
    • Export Citation
  • Zhu Y, Bond J & Thomas P 2003 Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proceedings of the National Academy of Sciences of the United States of America 100 22372242. (doi:10.1073/pnas.0436133100)

    • Search Google Scholar
    • Export Citation