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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

Norbert Weissmann
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Daniel Manz   *
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Daniela Buchspies
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Stephan Keller
2   Institute of Veterinary Physiology, Vetsuisse Faculty and Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
,
Tanja Mehling
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Robert Voswinckel
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Karin Quanz
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Hossein A. Ghofrani
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Ralph T. Schermuly
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Ludger Fink
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Werner Seeger
1   University of Giessen Lung Center, Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany
,
Max Gassmann
2   Institute of Veterinary Physiology, Vetsuisse Faculty and Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
› Author Affiliations Financial support: This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 547, project B7 (to N.W.) and the Swiss National Science Foundation (to M.G.).
Further Information

Publication History

Received: 11 February 2005

Accepted after major revision: 29 May 2005

Publication Date:
07 December 2017 (online)

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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

* Parts of the doctoral theses of Daniel Manz are incorporated into this report.


 

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