Abstract
Under normal conditions, the pulmonary circulation is a low-resistance, low-pressure system. Pulmonary hypertension (PH) is a heterogeneous condition that arises from a variety of etiologies affecting the pulmonary circulation and can be subdivided into five groups. Of these, pulmonary arterial hypertension (PAH) is the most severe, with a 5-year mortality rate near 40%. The development of PAH can be associated with various pathogenic or genetic causes, and, possibly because of this complexity, the mechanisms causing the disease are still incompletely understood. Female sex is perhaps one of the most well-established risk factors for the development of PAH, although over the past three decades, it has become increasingly clear that there are also important sex-based differences in PAH severity, response to treatment, and mortality. In this chapter, we will describe the preclinical and patient data underlying our current understanding of sex-based differences in PAH, discuss the clinical implications of these data, and point to future directions for research and patient care.
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References
Ahting U, Mayr JA, Vanlander AV, Hardy SA, Santra S, Makowski C, Alston CL, Zimmermann FA, Abela L, Plecko B, Rohrbach M, Spranger S, Seneca S, Rolinski B, Hagendorff A, Hempel M, Sperl W, Meitinger T, Smet J, Taylor RW, Van Coster R, Freisinger P, Prokisch H, Haack TB (2015) Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. Front Genet 6:123. https://doi.org/10.3389/fgene.2015.00123
Argiento P, Vanderpool RR, Mulè M, Russo MG, D'Alto M, Bossone E, Chesler NC, Naeije R (2012) Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest 142(5):1158–1165. https://doi.org/10.1378/chest.12-0071
Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA 3rd (2009) Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J 34(5):1093–1099. https://doi.org/10.1183/09031936.00010409
Austin ED, Hamid R, Hemnes AR, Loyd JE, Blackwell T, Yu C, Phillips Iii JA, Gaddipati R, Gladson S, Gu E, West J, Lane KB (2012) BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol Sex Differ 3(1):6. https://doi.org/10.1186/2042-6410-3-6
Baird GL, Archer-Chicko C, Barr RG, Bluemke DA, Foderaro AE, Fritz JS, Hill NS, Kawut SM, Klinger JR, Lima JAC, Mullin CJ, Ouyang P, Palevsky HI, Palmisicano AJ, Pinder D, Preston IR, Roberts KE, Smith KA, Walsh T, Whittenhall M, Ventetuolo CE (2018) Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension. Eur Respir J 51(6). https://doi.org/10.1183/13993003.00467-2018. PMCID: PMC6469347 https://erj.ersjournals.com/content/51/6/1800467
Badawi AF, Cavalieri EL, Rogan EG (2001) Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism 50(9):1001–1003. https://doi.org/10.1053/meta.2001.25592
Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD (2010) Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 137(2):376–387. https://doi.org/10.1378/chest.09-1140
Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 334(5):296–301. https://doi.org/10.1056/nejm199602013340504
Barst RJ, Channick R, Ivy D, Goldstein B (2012) Clinical perspectives with long-term pulsed inhaled nitric oxide for the treatment of pulmonary arterial hypertension. Pulm Circ 2(2):139–147. https://doi.org/10.4103/2045-8932.97589
Behan M, Wenninger JM (2008) Sex steroidal hormones and respiratory control. Respir Physiol Neurobiol 164(1-2):213–221. https://doi.org/10.1016/j.resp.2008.06.006
Chen X, Talati M, Fessel JP, Hemnes AR, Gladson S, French J, Shay S, Trammell A, Phillips JA, Hamid R, Cogan JD, Dawson EP, Womble KE, Hedges LK, Martinez EG, Wheeler LA, Loyd JE, Majka SJ, West J, Austin ED (2016) Estrogen metabolite 16α-hydroxyestrone exacerbates bone morphogenetic protein receptor Type II-associated pulmonary arterial hypertension through MicroRNA-29-mediated modulation of cellular metabolism. Circulation 133(1):82–97. https://doi.org/10.1161/CIRCULATIONAHA.115.016133
Chen X, Austin ED, Talati M, Fessel JP, Farber-Eger EH, Brittain EL, Hemnes AR, Loyd JE, West J (2017) Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects. Eur Respir J 50(2):1602337. https://doi.org/10.1183/13993003.02337-2016
Chester AH, Yacoub MH (2014) The role of endothelin-1 in pulmonary arterial hypertension. Glob Cardiol Sci Pract 2014(2):62–78. https://doi.org/10.5339/gcsp.2014.29
Dai Z, Zhu MM, Peng Y, Machireddy N, Evans CE, Machado R, Zhang X, Zhao YY (2018) Therapeutic targeting of vascular remodeling and right heart failure in pulmonary arterial hypertension with a HIF-2α inhibitor. Am J Respir Crit Care Med 198(11):1423–1434. https://doi.org/10.1164/rccm.201710-2079OC
de Raaf MA, Schalij I, Gomez-Arroyo J, Rol N, Happé C, de Man FS, Vonk-Noordegraaf A, Westerhof N, Voelkel NF, Bogaard HJ (2014) SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction. Eur Respir J 44(1):160. https://doi.org/10.1183/09031936.00204813
De Vries GJ, Rissman EF, Simerly RB, Yang L-Y, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP (2002) A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22(20):9005–9014. https://doi.org/10.1523/JNEUROSCI.22-20-09005.2002
Dingemanse J, van Giersbergen PL (2004) Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 43(15):1089–1115. https://doi.org/10.2165/00003088-200443150-00003
Earley S, Resta TC (2002) Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression. Am J Phys Lung Cell Mol Phys 283(1):L86–L93. https://doi.org/10.1152/ajplung.00476.2001
Escribano-Subias P, Blanco I, López-Meseguer M, Lopez-Guarch CJ, Roman A, Morales P, Castillo-Palma MJ, Segovia J, Gómez-Sanchez MA, Barberà JA (2012) Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J 40(3):596–603. https://doi.org/10.1183/09031936.00101211
Evans JD, Girerd B, Montani D, Wang XJ, Galiè N, Austin ED, Elliott G, Asano K, Grünig E, Yan Y, Jing ZC, Manes A, Palazzini M, Wheeler LA, Nakayama I, Satoh T, Eichstaedt C, Hinderhofer K, Wolf M, Rosenzweig EB, Chung WK, Soubrier F, Simonneau G, Sitbon O, Gräf S, Kaptoge S, Di Angelantonio E, Humbert M, Morrell NW (2016) BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med 4(2):129–137. https://doi.org/10.1016/s2213-2600(15)00544-5
Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HH, Stasch JP (2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5(9):755–768. https://doi.org/10.1038/nrd2038
Fessel JP, Chen X, Frump A, Gladson S, Blackwell T, Kang C, Johnson J, Loyd JE, Hemnes A, Austin E, West J (2013) Interaction between bone morphogenetic protein receptor type 2 and estrogenic compounds in pulmonary arterial hypertension. Pulm Circ 3(3):564–577. https://doi.org/10.1086/674312
Fishman AP (2001) Clinical classification of pulmonary hypertension. Clin Chest Med 22(3):385–391, vii. https://doi.org/10.1016/s0272-5231(05)70278-1
Forte P, Kneale BJ, Milne E, Chowienczyk PJ, Johnston A, Benjamin N, Ritter JM (1998) Evidence for a difference in nitric oxide biosynthesis between healthy women and men. Hypertension 32(4):730–734. https://doi.org/10.1161/01.hyp.32.4.730
Frantz RP, Schilz RJ, Chakinala MM, Badesch DB, Frost AE, McLaughlin VV, Barst RJ, Rosenberg DM, Miller DP, Hartline BK, Benton WW, Farber HW (2015) Hospitalization and survival in patients using epoprostenol for injection in the PROSPECT observational study. Chest 147(2):484–494. https://doi.org/10.1378/chest.14-1004
Frey R, Saleh S, Becker C, Mück W (2016) Effects of age and sex on the pharmacokinetics of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521). Pulm Circ 6(Suppl 1):S58–S65. https://doi.org/10.1086/685019
Frump AL, Goss KN, Vayl A, Albrecht M, Fisher A, Tursunova R, Fierst J, Whitson J, Cucci AR, Brown MB, Lahm T (2015) Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones. Am J Physiol Lung Cell Mol Physiol 308(9):L873–L890. https://doi.org/10.1152/ajplung.00006.2015
Frump AL, Albrecht ME, McClintick JN, Lahm T (2017) Estrogen receptor-dependent attenuation of hypoxia-induced changes in the lung genome of pulmonary hypertension rats. Pulm Circ 7(1):232–243. https://doi.org/10.1177/2045893217702055
Frump AL, Selej M, Wood JA, Albrecht M, Yakubov B, Petrache I, Lahm T (2018) Hypoxia upregulates estrogen receptor β in pulmonary artery endothelial cells in a HIF-1α-dependent manner. Am J Respir Cell Mol Biol 59(1):114–126. https://doi.org/10.1165/rcmb.2017-0167OC
Gabler NB, French B, Strom BL, Liu Z, Palevsky HI, Taichman DB, Kawut SM, Halpern SD (2012) Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest 141(1):20–26. https://doi.org/10.1378/chest.11-0404
Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C (2013a) Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369(4):319–329. https://doi.org/10.1056/NEJMoa1209657
Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ (2013b) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4):330–340. https://doi.org/10.1056/NEJMoa1209655
Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328(24):1732–1739. https://doi.org/10.1056/nejm199306173282402
Goncharova EA (2013) mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects. FASEB J 27(5):1796–1807. https://doi.org/10.1096/fj.12-222224
Hester J, Ventetuolo C, Lahm T (2019) Sex, gender, and sex hormones in pulmonary hypertension and right ventricular failure. Compr Physiol 10(1):125–170. https://doi.org/10.1002/cphy.c190011
Hoeper MM, Pletz MW, Golpon H, Welte T (2007) Prognostic value of blood gas analyses in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 29(5):944–950. https://doi.org/10.1183/09031936.00134506
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173(9):1023–1030. https://doi.org/10.1164/rccm.200510-1668OC
Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jaïs X, Montani D, Souza R, Simonneau G (2010) Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 122(2):156–163. https://doi.org/10.1161/circulationaha.109.911818
Ichimori H, Kogaki S, Takahashi K, Ishida H, Narita J, Nawa N, Baden H, Uchikawa T, Okada Y, Ozono K (2013) Drastic shift from positive to negative estrogen effect on bone morphogenetic protein signaling in pulmonary arterial endothelial cells under hypoxia. Circ J 77(8):2118–2126. https://doi.org/10.1253/circj.cj-12-0997
Jacobs W, van de Veerdonk MC, Trip P, de Man F, Heymans MW, Marcus JT, Kawut SM, Bogaard HJ, Boonstra A, Vonk Noordegraaf A (2014) The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest 145(6):1230–1236. https://doi.org/10.1378/chest.13-1291
Jiang B, Deng Y, Suen C, Taha M, Chaudhary KR, Courtman DW, Stewart DJ (2015) Marked strain-specific differences in the SU5416 rat model of severe pulmonary arterial hypertension. Am J Respir Cell Mol Biol 54(4):461–468. https://doi.org/10.1165/rcmb.2014-0488OC
Johansen AK, Dean A, Morecroft I, Hood K, Nilsen M, Loughlin L, Anagnostopoulou A, Touyz RM, White K, MacLean MR (2016) The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1. Pulm Circ 6(1):82–92. https://doi.org/10.1086/685023
Kawut SM, Al-Naamani N, Agerstrand C, Berman Rosenzweig E, Rowan C, Barst RJ, Bergmann S, Horn EM (2009) Determinants of right ventricular ejection fraction in pulmonary arterial hypertension. Chest 135(3):752–759. https://doi.org/10.1378/chest.08-1758
Kawut SM, Lima JA, Barr RG, Chahal H, Jain A, Tandri H, Praestgaard A, Bagiella E, Kizer JR, Johnson WC, Kronmal RA, Bluemke DA (2011) Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation 123(22):2542–2551. https://doi.org/10.1161/circulationaha.110.985515
Kawut SM, Archer-Chicko CL, DeMichele A, Fritz JS, Klinger JR, Ky B, Palevsky HI, Palmisciano AJ, Patel M, Pinder D, Propert KJ, Smith KA, Stanczyk F, Tracy R, Vaidya A, Whittenhall ME, Ventetuolo CE (2017) Anastrozole in pulmonary arterial hypertension. A randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 195(3):360–368. https://doi.org/10.1164/rccm.201605-1024OC
Klæstrup E, Trydal T, Pedersen JF, Larsen JM, Lundbye-Christensen S, Kristensen SR (2011) Reference intervals and age and gender dependency for arterial blood gases and electrolytes in adults. Clin Chem Lab Med 49(9):1495–1500. https://doi.org/10.1515/cclm.2011.603
Kleiger RE, Boxer M, Ingham RE, Harrison DC (1976) Pulmonary hypertension in patients using oral contraceptives. A report of six cases. Chest 69(2):143–147. https://doi.org/10.1378/chest.69.2.143
Kudryashova TV, Goncharov DA, Pena A, Kelly N, Vanderpool R, Baust J, Kobir A, Shufesky W, Mora AL, Morelli AE, Zhao J, Ihida-Stansbury K, Chang B, DeLisser H, Tuder RM, Kawut SM, Silljé HH, Shapiro S, Zhao Y, Goncharova EA (2016) HIPPO-integrin-linked kinase cross-talk controls self-sustaining proliferation and survival in pulmonary hypertension. Am J Respir Crit Care Med 194(7):866–877. https://doi.org/10.1164/rccm.201510-2003OC
Lahm T, Frump AL (2017) Toward harnessing sex steroid signaling as a therapeutic target in pulmonary arterial hypertension. Am J Respir Crit Care Med 195(3):284–286. https://doi.org/10.1164/rccm.201609-1906ED
Lahm T, Crisostomo PR, Markel TA, Wang M, Weil BR, Novotny NM, Meldrum DR (2008) The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: Potential new clinical implications for an old hormone. Crit Care Med 36(7):2174–2183
Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, Justice MJ, Brown MB, Van Demark M, Trulock KM, Dieudonne D, Reddy JG, Presson RG, Petrache I (2012) 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med 185(9):965–980. https://doi.org/10.1164/rccm.201107-1293OC
Lahm T, Tuder RM, Petrache I (2014) Progress in solving the sex hormone paradox in pulmonary hypertension. Am J Phys Lung Cell Mol Phys 307(1):L7–L26. https://doi.org/10.1152/ajplung.00337.2013
Lahm T, Frump AL, Albrecht ME, Fisher AJ, Cook TG, Jones TJ, Yakubov B, Whitson J, Fuchs RK, Liu A, Chesler NC, Brown MB (2016) 17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 311(2):L375–L388. https://doi.org/10.1152/ajplung.00132.2016
Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F, Hemnes AR, Kawut SM, Kline JA, Kolb TM, Mathai SC, Mercier O, Michelakis ED, Naeije R, Tuder RM, Ventetuolo CE, Vieillard-Baron A, Voelkel NF, Vonk-Noordegraaf A, Hassoun PM, American Thoracic Society Assembly on Pulmonary C (2018) Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. An official American thoracic society research statement. Am J Respir Crit Care Med 198(4):e15–e43. https://doi.org/10.1164/rccm.201806-1160ST
Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT (2003) Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 144(8):3382–3398. https://doi.org/10.1210/en.2003-0192
Leopold JA, Maron BA (2016) Molecular mechanisms of pulmonary vascular remodeling in pulmonary arterial hypertension. Int J Mol Sci 17(5):761. https://doi.org/10.3390/ijms17050761
Liu A, Schreier D, Tian L, Eickhoff JC, Wang Z, Hacker TA, Chesler NC (2014) Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension. Am J Phys Heart Circ Phys 307(3):H273–H283. https://doi.org/10.1152/ajpheart.00758.2013
Liu A, Hacker T, Eickhoff JC, Chesler NC (2017a) Estrogen preserves pulsatile pulmonary arterial hemodynamics in pulmonary arterial hypertension. Ann Biomed Eng 45(3):632–643. https://doi.org/10.1007/s10439-016-1716-1
Liu A, Philip J, Vinnakota KC, Van den Bergh F, Tabima DM, Hacker T, Beard DA, Chesler NC (2017b) Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension. Phys Rep 5(6):e13157. https://doi.org/10.14814/phy2.13157
Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA, Soubrier F, Trembath RC, Chung WK (2009) Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54(1 Supplement):S32. https://doi.org/10.1016/j.jacc.2009.04.015
Mair KM, Wright AF, Duggan N, Rowlands DJ, Hussey MJ, Roberts S, Fullerton J, Nilsen M, Loughlin L, Thomas M, MacLean MR (2014) Sex-dependent influence of endogenous estrogen in pulmonary hypertension. Am J Respir Crit Care Med 190(4):456–467. https://doi.org/10.1164/rccm.201403-0483OC
Mair KM, Yang XD, Long L, White K, Wallace E, Ewart M-A, Docherty CK, Morrell NW, MacLean MR (2015) Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 191(6):693–703. https://doi.org/10.1164/rccm.201410-1802OC
Mair KM, Harvey KY, Henry AD, Hillyard DZ, Nilsen M, MacLean MR (2019) Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension. Eur Respir J 53(6):1801524. https://doi.org/10.1183/13993003.01524-2018
Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, Simon MC (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1(6):393–399. https://doi.org/10.1016/j.cmet.2005.05.003
Marra AM, Egenlauf B, Ehlken N, Fischer C, Eichstaedt C, Nagel C, Bossone E, Cittadini A, Halank M, Gall H, Olsson KM, Lange TJ, Grünig E (2015) Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Int J Cardiol 195:19–26. https://doi.org/10.1016/j.ijcard.2015.05.105
Marra AM, Benjamin N, Eichstaedt C, Salzano A, Arcopinto M, Gargani L, DA M, Argiento P, Falsetti L, Di Giosia P, Isidori AM, Ferrara F, Bossone E, Cittadini A, Grünig E (2016) Gender-related differences in pulmonary arterial hypertension targeted drugs administration. Pharmacol Res 114:103–109. https://doi.org/10.1016/j.phrs.2016.10.018
Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, Thenappan T, Piao L, Zhang HJ, Pogoriler J, Chen Y, Morrow E, Weir EK, Rehman J, Archer SL (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110(11):1484–1497. https://doi.org/10.1161/circresaha.111.263848
Mathai SC, Hassoun PM, Puhan MA, Zhou Y, Wise RA (2015) Sex differences in response to tadalafil in pulmonary arterial hypertension. Chest 147(1):188–197. https://doi.org/10.1378/chest.14-0263
McMurtry IF, Frith CH, Will DH (1973) Cardiopulmonary responses of male and female swine to simulated high altitude. J Appl Physiol 35(4):459–462. https://doi.org/10.1152/jappl.1973.35.4.459
Medrek S, Sahay S, Zhao C, Selej M, Frost A (2020) Impact of race on survival in pulmonary arterial hypertension: results from the REVEAL registry. J Heart Lung Transplant 39(4):321–330. https://doi.org/10.1016/j.healun.2019.11.024
Miyauchi T, Yanagisawa M, Iida K, Ajisaka R, Suzuki N, Fujino M, Goto K, Masaki T, Sugishita Y (1992) Age- and sex-related variation of plasma endothelin-1 concentration in normal and hypertensive subjects. Am Heart J 123(4 Pt 1):1092–1093. https://doi.org/10.1016/0002-8703(92)90734-d
Moore LG, McMurtry IF, Reeves JT (1978) Effects of sex hormones on cardiovascular and hematologic responses to chronic hypoxia in rats. Proc Soc Exp Biol Med 158(4):658–662. https://doi.org/10.3181/00379727-158-40268
Morse JH, Horn EM, Barst RJ (1999) Hormone replacement therapy: a possible risk factor in carriers of familial primary pulmonary hypertension. Chest 116(3):847. https://doi.org/10.1378/chest.116.3.847
Mullin CJ, Khair RM, Damico RL, Kolb TM, Hummers LK, Hassoun PM, Steen VD, Mathai SC (2019) Validation of the REVEAL prognostic equation and risk score calculator in incident systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum 71(10):1691–1700. https://doi.org/10.1002/art.40918
Murphy E (2011) Estrogen signaling and cardiovascular disease. Circ Res 109(6):687–696. https://doi.org/10.1161/circresaha.110.236687
Nadadur RD, Umar S, Wong G, Eghbali M, Iorga A, Matori H, Partow-Navid R, Eghbali M (2012) Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension. J Appl Physiol (1985) 113(1):149–158. https://doi.org/10.1152/japplphysiol.01349.2011
Niihori M, Eccles CA, Kurdyukov S, Zemskova M, Varghese MV, Stepanova AA, Galkin A, Rafikov R, Rafikova O (2019) Rats with a human mutation of NFU1 develop pulmonary hypertension. Am J Respir Cell Mol Biol 62(2):231–242. https://doi.org/10.1165/rcmb.2019-0065OC
Olfert IM, Balouch J, Kleinsasser A, Knapp A, Wagner H, Wagner PD, Hopkins SR (2004) Does gender affect human pulmonary gas exchange during exercise? J Physiol 557(Pt 2):529–541. https://doi.org/10.1113/jphysiol.2003.056887
Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327(6122):524–526. https://doi.org/10.1038/327524a0
Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 338(8776):1173–1174. https://doi.org/10.1016/0140-6736(91)92033-x
Paulin R, Meloche J, Jacob MH, Bisserier M, Courboulin A, Bonnet S (2011) Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 301(5):H1798–H1809. https://doi.org/10.1152/ajpheart.00654.2011
Philip JL, Tabima DM, Wolf GD, Frump AL, Cheng T-C, Schreier DA, Hacker TA, Lahm T, Chesler NC (2019) Exogenous estrogen preserves distal pulmonary arterial mechanics and prevents pulmonary hypertension in rats. Am J Respir Crit Care Med 201(3):371–374. https://doi.org/10.1164/rccm.201906-1217LE
Pisarcik S, Maylor J, Lu W, Yun X, Undem C, Sylvester JT, Semenza GL, Shimoda LA (2013) Activation of hypoxia-inducible factor-1 in pulmonary arterial smooth muscle cells by endothelin-1. Am J Phys Lung Cell Mol Phys 304(8):L549–L561. https://doi.org/10.1152/ajplung.00081.2012
Polderman KH, Stehouwer CD, van Kamp GJ, Dekker GA, Verheugt FW, Gooren LJ (1993) Influence of sex hormones on plasma endothelin levels. Ann Intern Med 118(6):429–432. https://doi.org/10.7326/0003-4819-118-6-199303150-00006
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G (2013) Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369(9):809–818. https://doi.org/10.1056/NEJMoa1213917
Rabinovitch M, Gamble WJ, Miettinen OS, Reid L (1981) Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Phys 240(1):H62–H72. https://doi.org/10.1152/ajpheart.1981.240.1.H62
Rafikova O, Rafikov R, Meadows ML, Kangath A, Jonigk D, Black SM (2015) The sexual dimorphism associated with pulmonary hypertension corresponds to a fibrotic phenotype. Pulm Circ 5(1):184–197. https://doi.org/10.1086/679724
Rafikova O, James J, Eccles CA, Kurdyukov S, Niihori M, Varghese MV, Rafikov R (2020) Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability. Biol Sex Differ 11(1):11–11. https://doi.org/10.1186/s13293-020-00289-5
Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Péchoux C, Bogaard HJ, Dorfmüller P, Remy S, Lecerf F, Planté S, Chat S, Fadel E, Houssaini A, Anegon I, Adnot S, Simonneau G, Humbert M, Cohen-Kaminsky S, Perros F (2015) Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131(11):1006–1018. https://doi.org/10.1161/circulationaha.114.008750
Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, Diehl JH, Crow J, Long W (1990) Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 112(7):485–491. https://doi.org/10.7326/0003-4819-112-7-485
Rusiecki J, Rao Y, Cleveland J, Rhinehart Z, Champion HC, Mathier MA (2015) Sex and menopause differences in response to tadalafil: 6-minute walk distance and time to clinical worsening. Pulm Circ 5(4):701–706. https://doi.org/10.1086/683829
Ryan J, Dasgupta A, Huston J, Chen KH, Archer SL (2015a) Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med (Berl) 93(3):229–242. https://doi.org/10.1007/s00109-015-1263-5
Ryan JJ, Huston J, Kutty S, Hatton ND, Bowman L, Tian L, Herr JE, Johri AM, Archer SL (2015b) Right ventricular adaptation and failure in pulmonary arterial hypertension. Can J Cardiol 31(4):391–406. https://doi.org/10.1016/j.cjca.2015.01.023
Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148(3):399–408. https://doi.org/10.1016/j.cell.2012.01.021
Shapiro S, Traiger GL, Turner M, McGoon MD, Wason P, Barst RJ (2012) Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest 141(2):363–373. https://doi.org/10.1378/chest.10-3114
Sheel AW, Guenette JA (2008) Mechanics of breathing during exercise in men and women: sex versus body size differences? Exerc Sport Sci Rev 36(3):128–134. https://doi.org/10.1097/JES.0b013e31817be7f0
Shimoda LA, Laurie SS (2013) Vascular remodeling in pulmonary hypertension. J Mol Med (Berl) 91(3):297–309. https://doi.org/10.1007/s00109-013-0998-0
Shimoda LA, Laurie SS (2014) HIF and pulmonary vascular responses to hypoxia. J Appl Physiol (1985) 116(7):867–874. https://doi.org/10.1152/japplphysiol.00643.2013
Sidharta PN, Krähenbühl S, Dingemanse J (2015) Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension. Expert Opin Drug Metab Toxicol 11(3):437–449. https://doi.org/10.1517/17425255.2015.1000859
Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53(1):1801913. https://doi.org/10.1183/13993003.01913-2018
Simpkins JW, Yi KD, Yang S-H, Dykens JA (2010) Mitochondrial mechanisms of estrogen neuroprotection. Biochim Biophys Acta Gen Subj 1800(10):1113–1120. https://doi.org/10.1016/j.bbagen.2009.11.013
Simpson ER, Misso M, Hewitt KN, Hill RA, Boon WC, Jones ME, Kovacic A, Zhou J, Clyne CD (2005) Estrogen--the good, the bad, and the unexpected. Endocr Rev 26(3):322–330. https://doi.org/10.1210/er.2004-0020
Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV (2015) Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 373(26):2522–2533. https://doi.org/10.1056/NEJMoa1503184
Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF (2009) Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297(6):L1013–L1032. https://doi.org/10.1152/ajplung.00217.2009
Stewart DJ, Levy RD, Cernacek P, Langleben D (1991) Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 114(6):464–469. https://doi.org/10.7326/0003-4819-114-6-464
Sweeney L, Voelkel NF (2009) Estrogen exposure, obesity and thyroid disease in women with severe pulmonary hypertension. Eur J Med Res 14(10):433–442. https://doi.org/10.1186/2047-783x-14-10-433
Tamosiuniene R, Manouvakhova O, Mesange P, Saito T, Qian J, Sanyal M, Lin Y-C, Nguyen Linh P, Luria A, Tu Allen B, Sante Joshua M, Rabinovitch M, Fitzgerald Desmond J, Graham Brian B, Habtezion A, Voelkel Norbert F, Aurelian L, Nicolls Mark R (2018) Dominant role for regulatory T cells in protecting females against pulmonary hypertension. Circ Res 122(12):1689–1702. https://doi.org/10.1161/CIRCRESAHA.117.312058
Tang H, Babicheva A, McDermott KM, Gu Y, Ayon RJ, Song S, Wang Z, Gupta A, Zhou T, Sun X, Dash S, Wang Z, Balistrieri A, Zheng Q, Cordery AG, Desai AA, Rischard F, Khalpey Z, Wang J, Black SM, Garcia JGN, Makino A, Yuan JX (2018) Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. Am J Phys Lung Cell Mol Phys 314(2):L256–l275. https://doi.org/10.1152/ajplung.00096.2017
Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, Voelkel N, Tuder R (2001) Research communications-Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 15(2):427–438
Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D, Kelemen BW, Bacher AC, Shah AA, Hummers LK, Wigley FM, Russell SD, Saggar R, Saggar R, Maughan WL, Hassoun PM, Kass DA (2013) Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 6(5):953–963. https://doi.org/10.1161/circheartfailure.112.000008
Tello K, Richter MJ, Yogeswaran A, Ghofrani HA, Naeije R, Vanderpool R, Gall H, Tedford RJ, Seeger W, Lahm T (2020) Sex differences in right ventricular-pulmonary arterial coupling in pulmonary arterial hypertension. Am J Respir Crit Care Med 202(7):1042–1046. https://doi.org/10.1164/rccm.202003-0807LE
Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M (2007) A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J 30(6):1103–1110. https://doi.org/10.1183/09031936.00042107
Tofovic SP, Salah EM, Mady HH, Jackson EK, Melhem MF (2005) Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 46(4):430–437. https://doi.org/10.1097/01.fjc.0000175878.32920.17
Tofovic SP, Zhang X, Jackson EK, Dacic S, Petrusevska G (2006) 2-Methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension. Vasc Pharmacol 45(6):358–367. https://doi.org/10.1016/j.vph.2006.05.007
Tofovic SP, Zhang X, Zhu H, Jackson EK, Rafikova O, Petrusevska G (2008) 2-Ethoxyestradiol is antimitogenic and attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling. Vasc Pharmacol 48(4-6):174–183. https://doi.org/10.1016/j.vph.2008.02.001
Tofovic SP, Zhang X, Jackson EK, Zhu H, Petrusevska G (2009) 2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats. Vasc Pharmacol 51(2-3):190–197. https://doi.org/10.1016/j.vph.2009.06.002
Tofovic SP, Jones TJ, Bilan VP, Jackson EK, Petrusevska G (2010) Synergistic therapeutic effects of 2-methoxyestradiol with either sildenafil or bosentan on amelioration of monocrotaline-induced pulmonary hypertension and vascular remodeling. J Cardiovasc Pharmacol 56(5):475–483. https://doi.org/10.1097/FJC.0b013e3181f215e7
Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF (1999) Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159(6):1925–1932. https://doi.org/10.1164/ajrccm.159.6.9804054
Uguccioni M, Pulsatelli L, Grigolo B, Facchini A, Fasano L, Cinti C, Fabbri M, Gasbarrini G, Meliconi R (1995) Endothelin-1 in idiopathic pulmonary fibrosis. J Clin Pathol 48(4):330–334. https://doi.org/10.1136/jcp.48.4.330
Umar S, Iorga A, Matori H, Nadadur RD, Li J, Maltese F, van der Laarse A, Eghbali M (2011) Estrogen rescues preexisting severe pulmonary hypertension in rats. Am J Respir Crit Care Med 184(6):715–723. https://doi.org/10.1164/rccm.201101-0078OC
Umar S, Cunningham CM, Itoh Y, Moazeni S, Vaillancourt M, Sarji S, Centala A, Arnold AP, Eghbali M (2018) The Y chromosome plays a protective role in experimental hypoxic pulmonary hypertension. Am J Respir Crit Care Med 197(7):952–955. https://doi.org/10.1164/rccm.201707-1345LE
Ventetuolo CE, Ouyang P, Bluemke DA, Tandri H, Barr RG, Bagiella E, Cappola AR, Bristow MR, Johnson C, Kronmal RA, Kizer JR, Lima JA, Kawut SM (2011) Sex hormones are associated with right ventricular structure and function: the MESA-right ventricle study. Am J Respir Crit Care Med 183(5):659–667. https://doi.org/10.1164/rccm.201007-1027OC
Ventetuolo CE, Praestgaard A, Palevsky HI, Klinger JR, Halpern SD, Kawut SM (2014) Sex and haemodynamics in pulmonary arterial hypertension. Eur Respir J 43(2):523–530. https://doi.org/10.1183/09031936.00027613
Ventetuolo CE, Mitra N, Wan F, Manichaikul A, Barr RG, Johnson C, Bluemke DA, Lima JA, Tandri H, Ouyang P, Kawut SM (2016) Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function. Eur Respir J 47(2):553–563. https://doi.org/10.1183/13993003.01083-2015
Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM (2013) Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol 62(25 Suppl):D22–D33. https://doi.org/10.1016/j.jacc.2013.10.027
West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips JA, Lane K, Meyrick B, Loyd J (2008) Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genet 1:45. https://doi.org/10.1186/1755-8794-1-45
White K, Dempsie Y, Nilsen M, Wright AF, Loughlin L, MacLean MR (2010) The serotonin transporter, gender, and 17β oestradiol in the development of pulmonary arterial hypertension. Cardiovasc Res 90(2):373–382. https://doi.org/10.1093/cvr/cvq408
White K, Johansen Anne K, Nilsen M, Ciuclan L, Wallace E, Paton L, Campbell A, Morecroft I, Loughlin L, McClure John D, Thomas M, Mair Kirsty M, MacLean Margaret R (2012) Activity of the estrogen-metabolizing enzyme cytochrome P450 1B1 influences the development of pulmonary arterial hypertension. Circulation 126(9):1087–1098. https://doi.org/10.1161/CIRCULATIONAHA.111.062927
Xu D-Q, Luo Y, Liu Y, Wang J, Zhang B, Xu M, Wang Y-X, Dong H-Y, Dong M-Q, Zhao P-T, Niu W, Liu M-L, Gao Y-Q, Li Z-C (2010) Beta-estradiol attenuates hypoxic pulmonary hypertension by stabilizing the expression of p27kip1 in rats. Respir Res 11(1):182. https://doi.org/10.1186/1465-9921-11-182
Yager JD, Chen JQ (2007) Mitochondrial estrogen receptors – new insights into specific functions. Trends Endocrinol Metab 18(3):89–91. https://doi.org/10.1016/j.tem.2007.02.006
Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332(6163):411–415. https://doi.org/10.1038/332411a0
Yang S-H, Liu R, Perez EJ, Wen Y, Stevens SM, Valencia T, Brun-Zinkernagel A-M, Prokai L, Will Y, Dykens J, Koulen P, Simpkins JW (2004) Mitochondrial localization of estrogen receptor β. Proc Natl Acad Sci 101(12):4130–4135. https://doi.org/10.1073/pnas.0306948101
Zemskova M, Kurdyukov S, James J, McClain N, Rafikov R, Rafikova O (2020) Sex-specific stress response and HMGB1 release in pulmonary endothelial cells. PLoS One 15(4):e0231267–e0231267. https://doi.org/10.1371/journal.pone.0231267
Zhou Z, Zhou J, Du Y (2012) Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity. Mol Cell Proteomics 11(7):M111.011056. https://doi.org/10.1074/mcp.M111.011056
Acknowledgments
This work was supported by grants from NIH (HL073859 and HL126514 to LAS), the American Heart Association (AHA/19CDA34660173 to ALF), the American Lung Association (ALA/CA-629145 to ALF), and Actelion Pharmaceuticals (Entelligence Young Investigator Award to ALF).
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Frump, A.L., Shimoda, L.A. (2021). Sex Differences in Pulmonary Arterial Hypertension. In: Silveyra, P., Tigno, X.T. (eds) Sex-Based Differences in Lung Physiology. Physiology in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-63549-7_8
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