title: Congenital erythropoietin over-expression causes "anti-pulmonary hypertensive" structural and functional changes in mice, both in normoxia and hypoxia.
abstract: Acute alveolar hypoxia causes pulmonary vasoconstriction that matches lung perfusion to ventilation to optimize gas exchange. Chronic alveolar hypoxia induces pulmonary hypertension, characterized by increased muscularization of the pulmonary vasculature and right ventricular hypertrophy. Elevated erythropoietin (EPO) plasma levels increase hematocrit and blood viscosity and may affect structure and function of the pulmonary circulation. To differentiate between the direct effects of hypoxia and those linked to a hypoxia-induced increase in EPO/hematocrit levels, we investigated the lung vasculature in transgenic mice constitutively over-expressing EPO (termed tg6) upon exposure to normoxia and chronic hypoxia. Despite increased hematocrit levels (approximately 0.86),tg6 mice kept in normoxia did not develop selective right ventricular hypertrophy. The portion of vessels with a diameter of 51-95 microm and >155 microm was increased whereas the portion of small vessels (30-50 microm) was decreased. Pulmonary vascular resistance and the strength of hypoxic vasoconstriction measured in isolated perfused lungs were decreased. Vasoconstrictions induced by the thromboxane mimetic U46619 tended to be reduced. After chronic hypoxia (FiO2 = 0.10, 21 days), vascular resistance and vasoconstrictor responses to acute hypoxia and U46619 were reduced in tg6 mice compared to wildtype controls. Chronic hypoxia increased the degree of pulmonary vascular muscularization in wildtype but not in tg6 mice that already exhibited less muscularization in normoxia. In conclusion, congenital over-expression of EPO exerts an "anti-pulmonary hypertensive" effect, both structurally and functionally, particularly obvious upon chronic hypoxia.
authors.affiliation: University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany. Norbert.Weissmann@innere.med.uni-giessen.de
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Manz
authors.forename: Daniela
authors.initials: D
authors.lastname: Buchspies
authors.forename: Stephan
authors.initials: S
authors.lastname: Keller
authors.forename: Tanja
authors.initials: T
authors.lastname: Mehling
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
authors.forename: Karin
authors.initials: K
authors.lastname: Quanz
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure; D001808:Blood Vessels / Q000473:pathology; D001809:Blood Viscosity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000097:blood / Q000235:genetics / Q000502:physiology*; D006400:Hematocrit; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015854:Up-Regulation; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D014662:Vasoconstrictor Agents; D004921:Erythropoietin; D019323:omega-N-Methylarginine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D001241:Aspirin