Cerebral angiogenic factors, angiogenesis, and physiological response to chronic hypoxia differ among four commonly used mouse strains

Abstract

Angiogenesis is a critical element for adaptation to low levels of oxygen and occurs following long-term exposure to mild hypoxia in rats. To test whether a similar response in mice occurs, CD1, 129/Sv, C57Bl/6, and Balb/c mice were exposed to 10% oxygen for up to 3 wk. All mice showed significant increases in the percentage of packed red blood cells, and CD1 and 129/Sv mice showed increased respiration frequency and minute volume, common physiological measures of hypoxia. Significant angiogenesis was observed in all strains except Balb/c following 3-wk exposure to chronic hypoxia. CD1 hypoxic mice had the largest increase (88%), followed by C57Bl/6 (48%), 129/Sv (41%), and Balb/c (12%), suggesting that some mice undergo more remodeling than others in response to hypoxia. Protein expression analysis of vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1 and Ang2, and Tie2 were examined to determine whether regulation of different angiogenic proteins could account for the differences observed in hypoxia-induced angiogenesis. CD1 mice showed the strongest upregulation of VEGF, Ang2, Ang1, and Tie2, whereas Balb/c had only subtle increases in VEGF and no change in the other proteins. C57Bl/6 mice showed a regulatory response that fell between the CD1 and Balb/c mice, consistent with the intermediate increase in angiogenesis. Our results suggest that genetic heterogeneity plays a role in angiogenesis and regulation of angiogenic proteins and needs to be accounted for when designing and interpreting experiments using transgenic mice and when studying in vivo models of angiogenesis.

Chronic Exposure to Dietary Sterol Glucosides is Neurotoxic to Motor Neurons and Induces an ALS–PDC Phenotype

“…The results demonstrated that strain specific outcomes occur following BSSG exposure that is similar to that following cycad feeding (Wilson et al 2005a). Strain-dependent outcomes have also been noted for streptozotocin treatment (Sugimoto et al 2007), hypoxia (Ward et al 2007), exposure to cannabinoid receptor agonist (Hoffman et al 2005), rinderpest virus (RPV), peste des petits ruminants virus (PPRV) (Galbraith et al 2002), and naloxone (Navarro et al 1991). Although no behavioral deficits were observed in our second in vivo study, there was significant motor neuron loss that was progressive with increasing survival times.…”

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal

“…30 However, after a sublethal chronic hypoxic insult we and others have found that the CD-1 mice exhibit a more robust recovery compared with C57 mice (examining physiological parameters, HIF-1␣, and downstream signaling pathway components, angiogenesis, NSC proliferation, and apoptosis). 14,31 These data prompted us to investigate whether these biochemical and behavioral differences would be correlated with HIF-1␣ mRNA and/or protein levels and subcellular localization. Real-time RT-PCR and Western blot data revealed that HIF-1␣ mRNA was higher in CD-1 NSC lysates than in C57 NSC lysates after reduced O 2 conditions (Figure 2A), whereas HIF-1␣ protein expression was higher in CD-1 NSC lysates compared with C57 NSC lysates under both 20% and 5% O 2 culture conditions ( Figure 2B).…”

Adaptations to Chronic Hypoxia Combined with Erythropoietin Deficiency in Cerebral and Cardiac Tissues

“…With longer hypoxic exposure, polycythemia and cerebral angiogenesis take place to enhance cerebral oxygenation, while cerebral NO level returns to basal value [23,24]. Indeed, in a chronic hypoxic challenge to the central nervous system, the cerebral cortex is known to undergo a signiicant cerebrovascular remodeling, in order to preserve tissue oxygen and energy supply [24][25][26][27][28][29]. These microvascular changes occur relatively late compared to the physiological adaptations [30].…”

“…Brain angiogenesis also requires additional pro-angiogenic factors such as Ang-2. Ang-2, which is not constitutively expressed under normoxic conditions, is upregulated in rat and mouse endothelial cells following hypoxia [28,38]. Ang-2 induction during hypoxia is known to occur independently of HIF-1 and is due to cyclooxygenase-2 (COX-2) enzyme activity [42,43].…”