Department of Anatomy, Case Western Reserve University, Cleveland, OH, USA.
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
Adv Exp Med Biol. 2013;789:29-35. doi: 10.1007/978-1-4614-7411-1_5.
The partial pressure of oxygen in the brain parenchyma is tightly controlled, and normal brain function is delicately sensitive to continuous and controlled oxygen delivery. The objective of this study was to determine brain angiogenic adaptive changes during chronic normobaric hyperoxia and hypercapnia in mice. Four-month-old C56BL/6 J mice were kept in a normobaric chamber at 50 % O2 and 2.5 % CO2 for up to 3 weeks. Normoxic littermates were kept adjacent to the chamber and maintained on the same schedule. Physiological variables were measured at time points throughout the 3 weeks or when the mice were sacrificed. Freshly collected or fixed brain specimens were analyzed by Western blot analysis and immunohistochemistry (IHC). We found significant accumulation of hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) and increased expression of erythropoietin (EPO), cyclooxygenase-2 (COX-2), and angiopoietin-2 (Ang-2) in hyperoxia and hypercapnia. Conversely, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (KDR/Flk-1), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), and prolyl hydroxylase-2 (PHD-2) expressions were decreased in hyperoxia and hypercapnia. Capillary density was significantly diminished by the end of the 3rd week of hyperoxia and hypercapnia as compared to control. We conclude that HIF-independent mechanisms contribute to brain capillary density modulation that is continuously adjusted in accordance with tissue oxygen tension.
脑实质的氧分压受到严格控制，正常的脑功能对持续和受控的氧输送非常敏感。本研究的目的是确定慢性常压高氧和高碳酸血症期间小鼠脑血管生成适应性变化。将 4 月龄 C56BL/6 J 小鼠置于 50% O2 和 2.5% CO2 的常压室中长达 3 周。将正常氧合的同窝仔鼠饲养在邻近的室内，并按照相同的时间表饲养。在整个 3 周或处死小鼠时测量生理变量。通过 Western blot 分析和免疫组织化学（IHC）分析新鲜采集或固定的脑标本。我们发现缺氧诱导因子 1α 和 2α（HIF-1α 和 HIF-2α）明显积聚，促红细胞生成素（EPO）、环加氧酶-2（COX-2）和血管生成素-2（Ang-2）表达增加在高氧和高碳酸血症中。相反，血管内皮生长因子（VEGF）和 VEGF 受体-2（KDR/Flk-1）、过氧化物酶体增殖物激活受体γ共激活物 1-α（PGC-1α）和脯氨酰羟化酶-2（PHD-2）的表达在高氧和高碳酸血症中减少。与对照组相比，在高氧和高碳酸血症的第 3 周末，毛细血管密度显著降低。我们的结论是，HIF 非依赖性机制有助于脑毛细血管密度的调节，该调节与组织氧张力持续调整。
