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Norbert Weissmann, Daniel Manz, Daniela Buchspies, Stephan Keller, Tanja Mehling, Robert Voswinckel, Karin Quanz, Hossein A. Ghofrani, Ralph T. Schermuly, Ludger Fink, Werner Seeger, Max Gassmann, Friedrich Grimminger
Congenital erythropoietin over-expression causes anti-pulmonary hypertensive structural and functional changes in mice, both in normoxia and hypoxia
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 (0.86), tg6 mice kept in normoxia did not develop selective right ventricular hypertrophy. The portion of vessels with a diameter of 5195 m and >155 m was increased whereas the portion of small vessels (3050 m) 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, 21days), 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.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 94, 09/2005
Pages: 630 - 638