Reduced Cerebral Blood Flow but Elevated Cerebral Glucose Metabolic Rate in Erythropoietin Overexpressing Transgenic Mice with Excessive Erythrocytosis

Abstract

To examine the impact of excessive erythrocytosis on local cerebral blood flow (CBF) and cerebral glucose metabolic rate (CMRglc), we made use of our constitutively erythropoietin (Epo)-overexpressing transgenic mouse line (tg-6) that reach a mean hematocrit of 0.87. Compared with wild-type (wt) control siblings, CBF decreased by 44% in tg-6 mice, while upon hemodilution (tg-6-HD) to a physiologic hematocrit (e.g., 0.44) tg-6-HD mice returned the CBF to wt levels. Cerebral blood flow was determined in another transgenic mouse line that overexpresses human Epo in the brain only (tg-21): CBF increased by 17% compared with wt controls. However, oxygen delivery was similar in all four mouse groups tested (wt, tg-6, tg-6-HD and tg-21). Mean CMRglc was higher in tg-6 (+72%), tg-6-HD mice (+43%) and tg-21 (+22%) than in wt mice. Local CMRglc was higher in all 40 brain regions in tg-6 but only in 15 and 8 regions in tg-6-HD and tg-21 mice. These results show that prolonged increases in hematocrit did not alter cerebral oxygen delivery at a decreased CBF and increased CMRglc. Hemodilution suggests that high blood viscosity is a cause of the decrease in CBF and partly of the increase in CMRglc. Cerebral glucose metabolic rate may also be increased by a direct effect of Epo in the brain (tg-21 mice).