9 Unexpectedly, the blood pressure was not elevated nor was the cardiac output altered. 21 In contrast, in our tg mice an overexpression of human Epo induced excessive erythrocytosis independent of hypoxia and resulted in a 10- to 12-fold elevation of Epo plasma levels. Remarkably, this finely controlled regulation of Epo gene expression still occurs after decades of weekly exposure of men to intermittent hypoxia. 17 Reduced oxygen supply increases Epo synthesis through stabilization of the hypoxia-inducible factor-1α (HIF-1α) (reviewed in Hofer et al, 18 Semenza, 19 and Wenger 20). 11, 12 In addition, Epo is also expressed in neuronal cells, 13 can cross the blood-brain barrier, 14 and displays a protective effect against cerebral stroke 14-16 and light-induced retinal degeneration. Physiologically, Epo is produced in the fetal liver and adult kidney and primarily stimulates proliferation, differentiation, and maturation of erythroid progenitor cells (erythropoiesis). Thus, we generated a transgenic (tg) mouse line that, due to overexpression of human Epo cDNA, reaches hematocrit values up to 0.9 during the first 8 to 9 postnatal weeks. Due to the lack of a suitable model, however, there are few data available on adaptive mechanisms to excessive erythrocytosis in vivo. Because the blood's flow resistance is regulated mainly by the radius of the vessel and the whole-blood viscosity (reviewed in Pearson and Path 8) it is conceivable to expect that adaptation to highly increased hematocrit levels involves vasodilation and reduced viscosity. 6 These and other reports 7 indicate that adaptive mechanisms to excessive erythrocytosis exist. 4 Excessive erythrocytosis is also found in sports medicine: an endurance athlete with an autosomal dominant erythrocytosis 5 resulting in hematocrit levels up to 0.68 has won several Olympic gold medals in the past. 3 One should keep in mind, however, that adaptive mechanisms of high altitude dwellers might be population dependent as recently shown by differences in nitric oxide (NO) metabolism of the lung in Tibetans and Bolivian Aymara. 2 In keeping with this, Peruvian miners living and working at extreme altitude and exposed to cobalt (known to induce Epo expression) have been found to reach hematocrit levels of 0.75 to 0.91. One case report describes a Chilean miner working at 5950 m above sea level who reached an hematocrit level of 0.75 without showing impaired health conditions or reduced physical activity. 1 However, several reports demonstrate that some individuals can cope with excessive erythrocytosis. Severe elevation of the hematocrit level is often associated with hypertension and thromboembolism, leading to severe clinical complications and frequently to death. High hematocrit levels are observed in patients suffering from erythrocytoses such as polycythemia vera and chronic mountain sickness, as well as in lowlanders at high altitude and erythropoietin (Epo)–abusing athletes.
Apart from the nitric oxide–mediated vasodilation we reported earlier, adaptation to high hematocrit levels in tg mice involves regulated elevation of blood viscosity by increasing erythrocyte flexibility. This moderate increase in viscosity is explicable by the up to 3-fold higher elongation of tg erythrocytes at physiologic shear rates. Although plasma viscosity did not differ between tg and wt mice, tg whole-blood viscosity increased to a lower degree (4-fold) than expected from corresponding hemoconcentrated wt blood (8-fold). In tg mice, plasma volume was not elevated whereas blood volume was up to 25% of the body weight compared with 8% in wild-type (wt) siblings. Tg mice showed doubled reticulocyte counts and an increased mean corpuscular volume. Upon splenectomy, hematocrit values in tg mice decreased from 0.89 to 0.62. Extramedullar erythropoiesis occurred in the tg spleen, leading to splenomegaly. We analyzed adaptive mechanisms to excessive erythrocytosis in our transgenic (tg) mice that, due to hypoxia-independent erythropoietin (Epo) overexpression, reached hematocrit values of 0.8 to 0.9 without alteration of blood pressure, heart rate, or cardiac output. However, some individuals such as high altitude dwellers cope well with an increased hematocrit level. Severe elevation of red blood cell number is often associated with hypertension and thromboembolism resulting in severe cardiovascular complications.
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