Regular physical activity is associated with a decrease of cerebrovascular and cardiovascular events, which may relate to enhanced endothelium-dependent vasodilation. Here, we provide evidence that physical activity protects against ischemic stroke via mechanisms related to the upregulation of endothelial nitric oxide synthase (eNOS) in the vasculature. Voluntary training on running wheels or exercise on a treadmill apparatus for 3 weeks, respectively, reduced cerebral infarct size and functional deficits, improved endothelium-dependent vasorelaxation, and augmented cerebral blood flow in wild-type mice. The neuroprotective effects of physical training were completely absent in eNOS-deficient mice, indicating that the enhanced eNOS activity by physical training was the predominant mechanism by which this modality protects against cerebral injury. Our results suggest that physical activity not only decreases stroke risk, but also provides a prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia.

Glucose, the major fuel in the brain, is transported across the cell membranes by facilitated diffusion mediated by glucose transporter proteins. Essentially two types of glucose transporters are localized in the membranes of brain endothelial cells, astrocytes, and neurons. Their densities are well adjusted to changes in local energy demand.

Severe elevation of red blood cell number is often associated with hypertension and thromboembolism resulting in severe cardiovascular complications. However, some individuals such as high altitude dwellers cope well with an increased hematocrit level. 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. Extramedullar erythropoiesis occurred in the tg spleen, leading to splenomegaly. Upon splenectomy, hematocrit values in tg mice decreased from 0.89 to 0.62. Tg mice showed doubled reticulocyte counts and an increased mean corpuscular volume. 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. Although plasma viscosity did not differ between tg and wt mice, tg wholeblood 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 tg erythrocytes at physiologic shear rates. Apart from the nitric oxide-mediated vasodilation we reported earlier, adaptation to high hematocrit levels in tg mice involves regulated ele- IntroductionHigh 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. Severe elevation of the hematocrit level is often associated with hypertension and thromboembolism, leading to severe clinical complications and frequently to death. 1 However, several reports demonstrate that some individuals can cope with excessive erythrocytosis. 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. 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. 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. 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. 6 These and other reports 7 indicate that adaptive mechanisms to excessive erythrocytosis exist. 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 vi...