Adaptive mechanisms in mice constitutively overexpressing erythropoietin

Abstract

Oxygen supply of mammalian tissues requires a sufficient number of red blood cells that is regulated by erythropoietin (Epo). Although extreme hematocrit values may result in threatening cardiovascular complications, some high altitude dwellers cope well with extreme hematocrit values. To investigate adaptive mechanisms to excessive erythrocytosis, we generated transgenic (tg6) mice that, due to constitutive expression of human Epo, reach hematocrit values around 0.85. Tg6 mice had signs of chronic heart failure (cardiac dilatation, increased central venous pressure) but normal blood pressure, heart rate and cardiac output. Plasma volume was unchanged, whereas blood volume was as much as 25% of the body weight in tg6 mice compared to 8% in wildtype (wt) siblings. While plasma viscosity did not differ between tg6 and wt, tg6 whole-blood viscosity increased to a lower degree (fourfold) than expected from correspondingly hemoconcentrated wt blood (eightfold) due to an up to threefold higher flexibility of tg6 erythrocytes. The fact that our tg6 mice show nitric oxide-mediated vasodilatation, too, implies different adaptive mechanisms acting in parallel to limit the strain on the heart in excessive erythrocytosis. However, these mechanisms appear to be exhausted already under normal conditions since tg6 mice are not able to compensate properly for exercise and have a reduced life expectancy.