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Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAg(h)) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAg(h) mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1alpha, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAg(h) mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1alpha, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAg(h) mice developed cerebral angiogenesis through the HIF-1alpha/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAg(h), the decrease in HIF-1alpha, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.

The present study compared the hemorheological properties between Epo-TAgh mice (a model of erythropoietin deficient mice) and wild-type (WT) control mice. Blood viscosity was determined at several shear rates using a cone-plate viscometer at native and adjusted hematocrit (i.e. 40%). Red blood cell (RBC) deformability was measured by ecktacytometry at several shear stresses and RBC aggregation properties by backscattered technique at adjusted hematocrit (i.e. 40%). Epo-TAgh mice had severe anemia (very low hematocrit), decreased blood viscosity at native hematocrit and slightly reduced RBC deformability at high shear stresses in comparison with WT mice. Blood viscosity at adjusted hematocrit (i.e. 40%) was not different between WT and Epo-TAgh mice. RBC aggregation did not differ between the two mice models. These findings suggest a role of erythropoietin in the regulation of RBC deformability. [ABSTRACT FROM AUTHOR]

Abstract: The involvement of erythropoietin in cardiac adaptation to acute and chronic (CHx) hypoxia was investigated in erythropoietin deficient transgenic (Epo-TAgh) and wild-type (WT) mice. Left (LV) and right ventricular functions were assessed by echocardiography and hemodynamics. HIF-1α, VEGF and Epo pathways were explored through RT-PCR, ELISA, Western blot and immunocytochemistry. Epo gene and protein were expressed in cardiomyocytes of WT mice in normoxia and hypoxia. Increase in blood hemoglobin, angiogenesis and functional cardiac adaptation occurred in CHx in WT mice, allowing a normal oxygen delivery (O2T). Epo deficiency induced LV hypertrophy, increased cardiac output (CO) and angiogenesis, but O2T remained lower than in WT mice. In CHx Epo-TAgh mice, LV hypertrophy, CO and O2T decreased. HIF-1α and Epo receptor pathways were depressed, suggesting that Epo-TAgh mice could not adapt to CHx despite activation of cardioprotective pathways (increased P-STAT-5/STAT-5). HIF/Epo pathway is activated in the heart of WT mice in hypoxia. Chronic hypoxia induced cardiac adaptive responses that were altered with Epo deficiency, failing to maintain oxygen delivery to tissues. [Copyright &y& Elsevier]

Previous studies suggest that chronic erythropoietin (Epo) deficiency in male mice does not alter normoxic/hypoxic ventilation. As effects of Epo are sex specific and as progesterone could be a respiratory stimulant, we evaluated the impact of Epo deficiency and its possible interaction with progesterone in ventilatory control in female mice during estrous cycle phases. Compared to wild type (WT) animals, Epo-TAg h female mice exhibited higher ventilation in hypoxia. However, when data were separated into luteal and follicular phases of the estrous cycle, basal ventilation and hypoxic ventilation were not different in both mice strains. As progesterone is known to be a potent respiratory stimulant, additional experiments were performed to elucidate its role. Interestingly, after mifepristone treatment, HVR was not modified in WT and Epo-TAg h mice, showing that the ventilatory stimulation observed in females was not directly mediated by progesterone. We conclude that Epo-TAg h female mice show no estrous stage-dependent increase of ventilatory control and progesterone independent response to hypoxia. [ABSTRACT FROM AUTHOR]