Excessive erythrocytosis and non-erythropoietic functions of erythropoietin

Excessive erythrocytosis is associated with hypertension and thromboembolism resulting in severe cardiovascular complications. The key player of regulating red blood cell number is erythropoietin (Epo) that controls erythropoiesis in an oxygen-dependent manner. To test the impact of hypoxia-independent expression of Epo, we generated a transgenic (tg) mouse line termed tg6 that, due to constitutive expression of human Epo, reached hematocrit values of 0.8 to 0.9 without alteration of blood pressure, heart rate or cardiac output. Extramedullar erythropoieses occurred in the tg spleen leading to splenomegaly. Upon splenectomy, hematocrit in tg mice decreased from 0.89 to 0.62. In tg mice plasma volume was not elevated whereas blood volume was 25% of the body weight compared to 8% in wildtype (wt) siblings. While plasma viscosity did not differ between tg and wt, tg whole-blood viscosity increased to a lower degree (4-fold) than expected from corresponding hemoconcentrated wt blood (8-fold). This moderate increase in viscosity is explicable by the up to 3-fold higher elongation of transgenic erythrocytes. Thus, apart from the nitric oxide-mediated vasodilatation we reported earlier, adaptation to high hematocrit in tg mice involves regulated elevation of blood viscosity by increasing erythrocyte flexibility.

Knowing that Epo exerts also non-erythropoietic but tissue-protective effects, we tested the impact of several insults on our tg6 mice. We observed that elevated Epo levels protected from light-induced (but not from inherited) retinal degeneration as well as from experimentally induced myocardial infarction. Finally, we provide evidence that upon exposure of tg6 mice to 6% oxygen, cerebral Epo regulated the hypoxic ventilatory response in a gender-dependent manner.