Structural and functional prevention of hypoxia-induced pulmonary hypertension by individualized exercise training in mice.
Pulmonary hypertension (PH) is a disease with a poor prognosis characterized by a vascular remodeling process and an increase in pulmonary vascular resistance. While a variety of reports demonstrated that exercise training exerts beneficial effects on exercise performance and quality of life in PH patients, it is not known how physical exercise affects vascular remodeling processes occurring in hypoxia-induced PH. Therefore, we investigated the effect of individualized exercise training on the development of hypoxia-induced PH in mice. Training effects were compared with pharmacological treatment with the phosphodiesterase 5 inhibitor Sildenafil or a combination of training plus Sildenafil. Trained mice who received Sildenafil showed a significantly improved walking distance (from 88.9 ± 8.1 to 146.4 ± 13.1 m) and maximum oxygen consumption (from 93.3 ± 2.9 to 105.5 ± 2.2% in combination with Sildenafil, to 102.2 ± 3.0% with placebo) compared with sedentary controls. Right ventricular systolic pressure, measured by telemetry, was at the level of healthy normoxic animals, whereas right heart hypertrophy did not benefit from training. Most interestingly, the increase in small pulmonary vessel muscularization was prevented by training. Respective counterregulatory processes were detected for the nitric oxide-soluble guanylate cyclase-phosphodiesterase system. We conclude that individualized daily exercise can prevent vascular remodeling in hypoxia-induced PH.
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany; Norbert.Weissmann@innere.med.uni-giessen.de.
Norbert
N
Weissmann
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Dorothea M
DM
Peters
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Christina
C
Klöpping
Department of Sports Medicine, Justus Liebig-University Giessen, Giessen, Germany;
Karsten
K
Krüger
Department of Sports Medicine, Justus Liebig-University Giessen, Giessen, Germany;
Christian
C
Pilat
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Susmitha
S
Katta
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Michael
M
Seimetz
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Hossein A
HA
Ghofrani
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Ralph T
RT
Schermuly
Division of Infectiology and Pneumology, Charité-Universitätsmedizin Berlin Medical Clinic, Berlin, Germany; and.
Martin
M
Witzenrath
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany; Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Werner
W
Seeger
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen, Germany;
Friedrich
F
Grimminger
Department of Sports Medicine, Justus Liebig-University Giessen, Giessen, Germany;
Frank C
FC
Mooren
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005081:Exercise Therapy; D017079:Exercise Tolerance; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000628:therapy*; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010805:Physical Conditioning, Animal; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D017725:Ventricular Pressure
D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D015105:3',5'-Cyclic-AMP Phosphodiesterases
Sildenafil; chronic hypoxia; maximal walking distance; pulmonary vascular remodeling; training