title: Gender differences in hypoxic acclimatization in cyclooxygenase-2-deficient mice.
abstract: The aim of this study was to determine the effect of cyclooxygenase-2 (COX-2) gene deletion on the adaptive responses during prolonged moderate hypobaric hypoxia. Wild-type (WT) and COX-2 knockout (KO) mice of both genders (3 months old) were exposed to hypobaric hypoxia (~0.4 ATM) or normoxia for 21 days and brain capillary densities were determined. Hematocrit was measured at different time intervals; brain hypoxia-inducible factor -1α(HIF-1α), angiopoietin 2 (Ang-2), brain erythropoietin (EPO), and kidney EPO were measured under normoxic and hypoxic conditions. There were no gender differences in hypoxic acclimatization in the WT mice and similar adaptive responses were observed in the female KO mice. However, the male KO mice exhibited progressive vulnerability to prolonged hypoxia. Compared to the WT and female KO mice, the male COX-2 KO mice had significantly lower survival rate and decreased erythropoietic and polycythemic responses, diminished cerebral angiogenesis, decreased brain accumulation of HIF-1α, and attenuated upregulation of VEGF, EPO, and Ang-2 during hypoxia. Our data suggest that there are physiologically important gender differences in hypoxic acclimatization in COX-2-deficient mice. The COX-2 signaling pathway appears to be required for acclimatization in oxygen-limiting environments only in males, whereas female COX-2-deficient mice may be able to access COX-2-independent mechanisms to achieve hypoxic acclimatization.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio kxx@case.edu.
authors.forename: Kui
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Girriso F
authors.initials: GF
authors.lastname: Benderro
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Tsipis
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: LaManna
mesh_terms: D000064:Acclimatization / Q000502:physiology*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012727:Sex Characteristics; D012737:Sex Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D051546:Cyclooxygenase 2
keywords: Capillary density; hypoxia‐induced angiogenesis; hypoxic adaptation; prolonged hypoxia; sex differences