Cancer research has transformed our view on cellular mechanisms for oxygen sensing. It has been documented that these mechanisms are important for maintaining animal tissues and life in environments where oxygen (O2) concentrations fluctuate. In adult animals, oxygen sensing is governed by the Hypoxia Inducible Factors (HIFs) that are stabilized at low oxygen concentrations (hypoxia). Cellular responses to hypoxia associates with cell immaturity (stemness) and proper tissue and organ development. During mammalian development, the initial uterine environment is hypoxic. However, during avian embryogenesis, O2 continuously equilibrates across the porous eggshell and the oxygenation status is more complex. Here, we investigate HIF dynamics and use microelectrodes to determine O2 concentrations within the egg and the embryo during the first four days of development. To determine the increased O2 consumption rates, we also obtain the O2 transport coefficient (DO2) of eggshell and associated inner and outer shell membranes, both directly (using microelectrodes in ovo for the first time) and indirectly (using water evaporation at 37.5°C for the first time). Our results demonstrate a distinct hypoxic phase (<5% O2) between day 1 and 2, concurring with the onset of HIF-α expression. This phase of hypoxia is demonstrably necessary for proper vascularization and survival. Our indirectly determined DO2 values are about 30% higher than those determined directly. A comparison with previously reported values indicates that this discrepancy may be real, reflecting that water vapor and O2 may be transported through the eggshell at different rates. Based on our obtained DO2 values, we demonstrate that increased O2 consumption of the growing embryo appears to generate the phase of hypoxia, which is also facilitated by the initially small gas cell and low membrane permeability. We infer that the phase of in ovo hypoxia facilitates correct avian development. The study highlights that insights from the cancer field pertaining to the importance of hypoxia can broadly inform our exploration of animal development and success.

中文翻译：

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禽胚胎生长产生的缺氧诱导HIF-α反应和关键血管形成

癌症研究已经改变了我们对氧传感细胞机制的看法。已有文献证明，这些机制对于在氧气（O2）浓度波动的环境中维持动物组织和生命至关重要。在成年动物中，氧感测受低氧诱导因子（HIF）的控制，该因子在低氧浓度（低氧）下稳定。细胞对缺氧的反应与细胞的不成熟（干性）以及适当的组织和器官发育有关。在哺乳动物发育过程中，最初的子宫环境是缺氧的。但是，在禽类胚胎发生过程中，O2在整个多孔蛋壳中持续平衡，并且氧化状态更为复杂。这里，我们研究了HIF动态，并在发育的前四天使用微电极确定了鸡蛋和胚胎中的O2浓度。为了确定增加的O2消耗率，我们还直接（间接使用卵中的微电极）和间接（使用37.5°C的水蒸发）获得蛋壳以及相关的内壳和外壳膜的O2传输系数（DO2）首次）。我们的结果表明，在第1天和第2天之间存在明显的缺氧阶段（<5％O2），与HIF-α表达的开始有关。缺氧的这一阶段对于适当的血管形成和生存是必不可少的。我们间接确定的DO2值比直接确定的DO2值高约30％。与先前报告的值进行比较表明，这种差异可能是真实的，反映出水蒸气和O2可能以不同的速率穿过蛋壳。基于我们获得的DO2值，我们证明生长中的胚胎的O2消耗增加似乎会产生缺氧阶段，最初的小气室和低膜通透性也促进了缺氧阶段。我们推断卵内缺氧的阶段有助于正确的禽类发育。该研究强调，来自癌症领域的关于缺氧重要性的见解可以广泛地指导我们对动物发育和成功的探索。最初较小的气室和较低的膜渗透性也促进了这一点。我们推断卵内缺氧的阶段有助于正确的禽类发育。该研究强调，来自癌症领域的关于缺氧重要性的见解可以广泛地指导我们对动物发育和成功的探索。最初较小的气室和较低的膜渗透性也促进了这一点。我们推断卵内缺氧的阶段有助于正确的禽类发育。该研究强调，来自癌症领域的关于缺氧重要性的见解可以广泛地指导我们对动物发育和成功的探索。