Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia

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

doi:10.1160/TH05-02-0104

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(03): 630-638
DOI: 10.1160/TH05-02-0104

Cell Signalling and Vessel Remodelling

Schattauer GmbH

Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia

Authors

Norbert Weissmann

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Daniel Manz^*

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Daniela Buchspies

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Stephan Keller

²Institute of Veterinary Physiology, Vetsuisse Faculty and Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
Tanja Mehling

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Robert Voswinckel

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Karin Quanz

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Hossein A. Ghofrani

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Ralph T. Schermuly

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Ludger Fink

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Werner Seeger

¹University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Max Gassmann

²Institute of Veterinary Physiology, Vetsuisse Faculty and Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland

Abstract

Summary

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 51–95 μm and >155 μm was increased whereas the portion of small vessels (30–50 μm) 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.

Keywords

Hypoxia - mouse - excessive erythrocytosis - vasoconstriction

Full Text

References

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