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-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.
Hasegawa
Jo
J
Department of Anesthesiology and Critical Care Medicine, University of Lübeck, Lübeck, Germany. suhlig@fz-borstel.de
Wagner
Klaus F
KF
Karp
Dörte
D
Li
Dechun
D
Shibata
Junpei
J
Heringlake
Matthias
M
Bahlmann
Ludger
L
Depping
Reinhard
R
Fandrey
Joachim
J
Schmucker
Peter
P
Uhlig
Stefan
S
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001809:Blood Viscosity; D004921:Erythropoietin; D006976:Hypertension, Pulmonary / Q000097:blood / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011086:Polycythemia / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D004921:Erythropoietin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid