Altered Pulmonary Vascular Reactivity in Mice with Excessive Erythrocytosis

Pulmonary vascular remodeling during chronic hypoxia may be the result of either oxygen deprivation or erythrocytosis. To separate experimentally the effects of hypoxia and erythrocytosis, we analyzed transgenic mice that constitutively overexpress the human erythropoietin gene in an oxygen-independ...

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Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2004-04, Vol.169 (7), p.829-835
Main Authors: Hasegawa, Jo, Wagner, Klaus F, Karp, Dorte, Li, Dechun, Shibata, Junpei, Heringlake, Matthias, Bahlmann, Ludger, Depping, Reinhard, Fandrey, Joachim, Schmucker, Peter, Uhlig, Stefan
Format: Article
Language:English
Subjects:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology
Analysis of Variance
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Biological and medical sciences
Blood Viscosity
Erythropoietin
Hypertension, Pulmonary - blood
Hypertension, Pulmonary - physiopathology
Hypoxia - physiopathology
Immunohistochemistry
Intensive care medicine
Lung - blood supply
Lung - drug effects
Lung - pathology
Medical sciences
Mice
Mice, Transgenic
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - pathology
Muscle, Smooth, Vascular - physiopathology
Polycythemia - physiopathology
Pulmonary Artery - drug effects
Pulmonary Artery - pathology
Pulmonary Artery - physiopathology
Vasoconstrictor Agents - pharmacology
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Summary:Pulmonary vascular remodeling during chronic hypoxia may be the result of either oxygen deprivation or erythrocytosis. To separate experimentally the effects of hypoxia and erythrocytosis, we analyzed transgenic mice that constitutively overexpress the human erythropoietin gene in an oxygen-independent manner. These mice are characterized by polycythemia but have normal blood pressure, heart rate, and cardiac output. In transgenic mice, pulmonary artery pressure (PAP) was increased in vivo but was reduced in blood-free perfused lungs. The thromboxane receptor agonist U46619 caused a smaller rise in PAP in isolated transgenic lungs than in lungs from wild-type mice. The transgenic pulmonary vasculature was characterized by elevated prostacyclin production, stronger endothelial nitric oxide synthase expression, and reduced pulmonary vascular smooth muscle thickness. The fact that transgenic polycythemic mice have marked pulmonary hypertension in vivo but not in vitro suggests that their pulmonary hypertension is due to the increased blood viscosity, thus supporting an independent role of polycythemia in the development of pulmonary hypertension. In addition, our findings indicate that the lungs of transgenic animals adapt to the high PAP by elevated synthesis of vasodilators and reduced vascular smooth muscle thickness that tend to reduce vascular tone and vascular responsiveness.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.200308-1154OC