Abstract
Pulmonary arterial hypertension (PAH) is caused by extensive pulmonary vascular remodeling that increases right ventricular (RV) afterload and leads to RV failure. PAH predominantly affects women; paradoxically, female PAH patients have better outcomes than men. The roles of estrogen in PAH remain controversial, which is referred to as “the estrogen paradox”. Here, we sought to determine the role of estrogen in pulsatile pulmonary arterial hemodynamic changes and its impact on RV functional adaption to PAH. Female mice were ovariectomized and replenished with estrogen or placebo. PAH was induced with SU5416 and chronic hypoxia. In vivo hemodynamic measurements showed that (1) estrogen prevented loss of pulmonary vascular compliance with limited effects on the increase of pulmonary vascular resistance in PAH; (2) estrogen attenuated increases in wave reflections in PAH and limited its adverse effects on PA systolic and pulse pressures; and (3) estrogen maintained the total hydraulic power and preserved transpulmonary vascular efficiency in PAH. This study demonstrates that estrogen preserves pulmonary vascular compliance independent of pulmonary vascular resistance, which provides a mechanical mechanism for ability of estrogen to delay disease progression without preventing onset. The estrogenic protection of pulsatile pulmonary hemodynamics underscores the therapeutic potential of estrogen in PAH.
Similar content being viewed by others
Abbreviations
- CI:
-
Cardiac index
- CO:
-
Cardiac output
- LV:
-
Left ventricle
- mPAP:
-
Mean pulmonary arterial pressure
- OVX:
-
Ovariectomy
- PA:
-
Pulmonary artery
- PAH:
-
Pulmonary arterial hypertension
- PCWP:
-
Pulmonary capillary wedge pressure
- PP:
-
Pulse pressure
- PWV:
-
Pulse wave velocity
- P f :
-
Forward pressure
- P b :
-
Backward pressure
- P b/P f :
-
Index of global wave reflection
- PVR:
-
Pulmonary vascular resistance
- RV:
-
Right ventricle
- SuHx:
-
Sugen-hypoxia exposure
- SV:
-
Stroke volume
- SV/PP:
-
Global arterial compliance
- tPVR:
-
Total pulmonary vascular resistance
- W t :
-
Total hydraulic power
- W o :
-
Oscillatory hydraulic power
- W o/W t :
-
Oscillatory power fraction
- CO/W t :
-
Transpulmonary vascular efficiency
- Z 0 :
-
Total vascular resistance
- Z C :
-
Characteristic impedance
- Γ = (Z 0 − Z C)/(Z 0 + Z C):
-
Pulse wave reflection
References
Aird, W. C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ. Res. 100:158–173, 2007.
Austin, E., A. Johansen, A. Alzoubi, T. Lahm, J. West, S. Tofovic, M. MacLean, and M. Oka. Gender, sex hormones and pulmonary hypertension. Pulm. Circ. 3:294, 2013.
Badesch, D. B., G. E. Raskob, C. G. Elliott, A. M. Krichman, H. W. Farber, A. E. Frost, R. J. Barst, R. L. Benza, T. G. Liou, and M. Turner. Pulmonary Arterial HypertensionBaseline Characteristics From the REVEAL Registry. CHEST J. 137:376–387, 2010.
Bellofiore, A., A. Roldán-Alzate, M. Besse, H. B. Kellihan, D. W. Consigny, C. J. Francois, and N. C. Chesler. Impact of acute pulmonary embolization on arterial stiffening and right ventricular function in dogs. Ann. Biomed. Eng. 41:195–204, 2013.
Borgdorff, M. A. J., M. G. Bartelds, P. Dickinson, M. Steendijk, M. de Vroomen, and R. M. F. Berger. Distinct loading conditions reveal various patterns of right ventricular adaptation. Am. J. Physiol. 305:H354–H364, 2013.
Chambliss, K. L., and P. W. Shaul. Estrogen modulation of endothelial nitric oxide synthase. Endocr. Rev. 23:665–686, 2002.
Cheifetz, I., D. M. Craig, F. H. Kern, D. R. Black, N. D. Hillman, W. J. Greeley, R. M. Ungerleider, P. K. Smith, and J. N. Meliones. Nitric oxide improves transpulmonary vascular mechanics but does not change intrinsic right ventricular contractility in an acute respiratory distress syndrome model with permissive hypercapnia. Crit. Care Med. 24:1554–1561, 1996.
de Jesus Perez, V. A. Making sense of the estrogen paradox in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 184:629–630, 2011.
Furuno, Y., Y. Nagamoto, M. Fujita, T. Kaku, S. Sakurai, and A. Kuroiwa. Reflection as a cause of mid-systolic deceleration of pulmonary flow wave in dogs with acute pulmonary hypertension: comparison of pulmonary artery constriction with pulmonary embolisation. Cardiovasc. Res. 25:118–124, 1991.
Grignola, J. C., F. Ginés, D. Bia, and R. Armentano. Improved right ventricular–vascular coupling during active pulmonary hypertension. Int. J. Cardiol. 115:171–182, 2007.
Humbert, M., O. Sitbon, A. Yaïci, D. Montani, D. S. O’Callaghan, X. Jaïs, F. Parent, L. Savale, D. Natali, S. Günther, A. Chaouat, F. Chabot, J.-F. Cordier, G. Habib, V. Gressin, Z.-C. Jing, R. Souza, and G. Simonneau. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur. Respir. J. 36:549–555, 2010.
Hunter, K. S., P.-F. Lee, C. J. Lanning, D. D. Ivy, K. S. Kirby, L. R. Claussen, K. C. Chan, and R. Shandas. Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pvr alone in pediatric patients with pulmonary hypertension. Am. Heart J. 155:166–174, 2008.
Jacobs, W., M. C. van de Veerdonk, P. Trip, F. de Man, M. W. Heymans, J. T. Marcus, S. M. Kawut, H.-J. Bogaard, A. Boonstra, and A. V. Noordegraaf. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest 145:1230–1236, 2014.
Kelly, R. P., R. Tunin, and D. A. Kass. Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ. Res. 71:490–502, 1992.
Kobs, R. W., N. E. Muvarak, J. C. Eickhoff, and N. C. Chesler. Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension. Am. J. Physiol. Heart Circ. Physiol. 288:H1209–H1217, 2005.
Kopeć, G., D. Moertl, P. Jankowski, A. Tyrka, B. Sobień, and P. Podolec. Pulmonary artery pulse wave velocity in idiopathic pulmonary arterial hypertension. Can. J. Cardiol. 29:683–690, 2013.
Lahm, T., M. Albrecht, A. J. Fisher, M. Selej, N. G. Patel, J. A. Brown, M. J. Justice, M. B. Brown, M. V. Demark, K. M. Trulock, D. Dieudonne, J. G. Reddy, R. G. Presson, and I. Petrache. 17β-estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor–mediated effects. Am. J. Respir. Crit. Care Med. 185:965–980, 2012.
Lankhaar, J.-W., N. Westerhof, T. J. C. Faes, C. T.-J. Gan, K. M. Marques, A. Boonstra, F. G. van den Berg, P. E. Postmus, and A. Vonk-Noordegraaf. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur. Heart J. 29:1688–1695, 2008.
Lankhaar, J.-W., N. Westerhof, T. J. C. Faes, K. M. J. Marques, J. T. Marcus, P. E. Postmus, and A. Vonk-Noordegraaf. Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am. J. Physiol. 291:H1731–H1737, 2006.
Limacher, M. C., J. A. Ware, M. E. O’Meara, G. C. Fernandez, and J. B. Young. Tricuspid regurgitation during pregnancy: Two-dimensional and pulsed doppler echocardiographic observations. Am. J. Cardiol. 55:1059–1062, 1985.
Liu, A., D. Schreier, L. Tian, J. C. Eickhoff, Z. Wang, T. A. Hacker, and N. C. Chesler. Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol. 307:H273–H283, 2014.
Liu, A., L. Tian, M. Golob, J. C. Eickhoff, M. Boston, and N. C. Chesler. 17β-estradiol attenuates conduit pulmonary artery mechanical property changes with pulmonary arterial hypertension. Hypertension 66:1082–1088, 2015.
Ross, R. V. M., M. R. Toshner, E. Soon, R. Naeije, and J. Pepke-Zaba. Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension. Am. J. Physiol. 305:H259–H264, 2013.
MacRitchie, A. N., S. S. Jun, Z. Chen, Z. German, I. S. Yuhanna, T. S. Sherman, and P. W. Shaul. Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ. Res. 81:355–362, 1997.
Mendelsohn, M. E., and R. H. Karas. The Protective Effects of Estrogen on the Cardiovascular System. N. Engl. J. Med. 340:1801–1811, 1999.
Mitchell, G. F., M. A. Pfeffer, N. Westerhof, and J. M. Pfeffer. Measurement of aortic input impedance in rats. Am. J. Physiol. 267:H1907–H1915, 1994.
Noordegraaf, A. V., and N. Galiè. The role of the right ventricle in pulmonary arterial hypertension. Eur. Respir. Rev. 20:243–253, 2011.
Peter, I., A. Kelley-Hedgepeth, G. S. Huggins, D. E. Housman, M. E. Mendelsohn, J. A. Vita, R. S. Vasan, D. Levy, E. J. Benjamin, and G. F. Mitchell. Association between arterial stiffness and variations in oestrogen-related genes. J. Hum. Hypertens. 23:636–644, 2009.
Presson, R. G., S. H. Audi, C. C. Hanger, G. M. Zenk, R. A. Sidner, J. H. Linehan, W. W. Wagner, and C. A. Dawson. Anatomic distribution of pulmonary vascular compliance. J. Appl. Physiol. 84:303–310, 1998.
Rogers, J. H., and S. F. Bolling. The tricuspid valve: current perspective and evolving management of tricuspid regurgitation. Circulation 119:2718–2725, 2009.
Russo, C., Z. Jin, V. Palmieri, S. Homma, T. Rundek, M. S. V. Elkind, R. L. Sacco, and M. R. D. Tullio. Arterial stiffness and wave reflection sex differences and relationship with left ventricular diastolic function. Hypertension 60:362–368, 2012.
Segers, P., E. R. Rietzschel, M. L. D. Buyzere, S. J. Vermeersch, D. D. Bacquer, L. M. V. Bortel, G. D. Backer, T. C. Gillebert, and P. R. Verdonck. Noninvasive (Input) impedance, pulse wave velocity, and wave reflection in healthy middle-aged men and women. Hypertension 49:1248–1255, 2007.
Shanahan, C. M., and P. L. Weissberg. Smooth muscle cell heterogeneity: patterns of gene expression in vascular smooth muscle cells in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol. 18:333–338, 1998.
Stefanadis, C. E., J. Tsiamis, and P. Toutouzas. Effect of estrogen on aortic function in postmenopausal women. Am. J. Physiol. 276:H658–H662, 1999.
Tabima, D. M., A. Roldan-Alzate, Z. Wang, T. A. Hacker, R. C. Molthen, and N. C. Chesler. Persistent vascular collagen accumulation alters hemodynamic recovery from chronic hypoxia. J. Biomech. 45:799–804, 2012.
Tedford, R. J., P. M. Hassoun, S. C. Mathai, R. E. Girgis, S. D. Russell, D. R. Thiemann, O. H. Cingolani, J. O. Mudd, B. A. Borlaug, M. M. Redfield, D. J. Lederer, and D. A. Kass. Pulmonary capillary wedge pressure augments right ventricular pulsatile loadingclinical perspective. Circulation 125:289–297, 2012.
Wang, S., L. P. Lee, and J. S. Lee. A linear relation between the compressibility and density of blood. J. Acoust. Soc. Am. 109:390–396, 2001.
Wang, Z., and N. C. Chesler. Pulmonary vascular wall stiffness: an important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm. Circ. 1:212–223, 2011.
Wang, Z., R. S. Lakes, M. Golob, J. C. Eickhoff, and N. C. Chesler. Changes in large pulmonary arterial viscoelasticity in chronic pulmonary hypertension. PLoS One 8:e78569, 2013.
Westerhof, N., P. Sipkema, G. C. V. D. Bos, and G. Elzinga. Forward and backward waves in the arterial system. Cardiovasc. Res. 6:648–656, 1972.
Xu, D. Q., Y. Luo, Y. Liu, J. Wang, B. Zhang, M. Xu, Y. X. Wang, H. Y. Dong, M. Q. Dong, P. T. Zhao, et al. Beta-estradiol attenuates hypoxic pulmonary hypertension by stabilizing the expression of p27kip1 in rats. Respir. Res. 11:182, 2010.
Yuan, P., W.-H. Wu, L. Gao, Z.-Q. Zheng, D. Liu, H.-Y. Mei, Z.-L. Zhang, and Z.-C. Jing. Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways. Eur. Respir. J. 41:1116–1125, 2013.
Acknowledgments
We thank Dr. Guoqing Song for performing in vivo hemodynamic measurement in mice. This work was supported by National Institutes of Health R01HL-086939 (to N.C. Chesler) and American Heart Association 13POST16910091 (to A. Liu).
Author information
Authors and Affiliations
Corresponding author
Additional information
Associate Editor Andreas Anayiotos oversaw the review of this article.
Rights and permissions
About this article
Cite this article
Liu, A., Hacker, T., Eickhoff, J.C. et al. Estrogen Preserves Pulsatile Pulmonary Arterial Hemodynamics in Pulmonary Arterial Hypertension. Ann Biomed Eng 45, 632–643 (2017). https://doi.org/10.1007/s10439-016-1716-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10439-016-1716-1