17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension.
17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies.
Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; tlahm@iu.edu.
Tim
T
Lahm
Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Andrea L
AL
Frump
Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Marjorie E
ME
Albrecht
Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, Indiana;
Amanda J
AJ
Fisher
Indiana Center for Vascular Biology and Medicine, Indianapolis, Indiana;
Todd G
TG
Cook
Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Thomas J
TJ
Jones
Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Bakhtiyor
B
Yakubov
Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana;
Jordan
J
Whitson
Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indianapolis, Indiana; and.
Robyn K
RK
Fuchs
Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, Wisconsin.
Aiping
A
Liu
Department of Biomedical Engineering, University of Wisconsin-Madison College of Engineering, Madison, Wisconsin.
Naomi C
NC
Chesler
Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indianapolis, Indiana; and.
M Beth
MB
Brown
D000222:Adaptation, Physiological; D000818:Animals; D062186:Arterial Pressure; D001343:Autophagy; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010101:Oxygen Consumption; D005082:Physical Exertion; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013318:Stroke Volume; D066253:Vascular Remodeling; D018497:Ventricular Dysfunction, Right; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
apoptosis; autophagy; endothelial nitric oxide synthase; fibrosis; sugen/hypoxia