Abstract
Hypoxia is a physiological or pathological condition of a deficiency of oxygen supply in the body as a whole or within a tissue. During hypoxia, tissues undergo a series of physiological responses to defend themselves against a low oxygen supply, including increased angiogenesis, erythropoiesis, and glucose uptake. The effects of hypoxia are mainly mediated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimeric transcription factor consisting of α and β subunits. HIF-1β is constantly expressed, whereas HIF-1α is degraded under normal oxygen conditions. Hypoxia stabilizes HIF-1α and the HIF complex, and HIF then translocates into the nucleus to initiate the expression of target genes. Hypoxia has been extensively studied for its role in promoting tumor progression, and emerging evidence also indicates that hypoxia may play important roles in physiological processes, including mammary development and lactation. The mammary gland exhibits an increasing metabolic rate from pregnancy to lactation to support mammary growth, lactogenesis, and lactation. This process requires increasing amounts of oxygen consumption and results in localized chronic hypoxia as confirmed by the binding of the hypoxia marker pimonidazole HCl in mouse mammary gland. We hypothesized that this hypoxic condition promotes mammary development and lactation, a hypothesis that is supported by the following several lines of evidence: i) Mice with an HIF-1α deletion selective for the mammary gland have impaired mammary differentiation and lipid secretion, resulting in lactation failure and striking changes in milk compositions; ii) We recently observed that hypoxia significantly induces HIF-1α-dependent glucose uptake and GLUT1 expression in mammary epithelial cells, which may be responsible for the dramatic increases in glucose uptake and GLUT1 expression in the mammary gland during the transition period from late pregnancy to early lactation; and iii) Hypoxia and HIF-1α increase the phosphorylation of signal transducers and activators of transcription 5a (STAT5a) in mammary epithelial cells, whereas STAT5 phosphorylation plays important roles in the regulation of milk protein gene expression and mammary development. Based on these observations, hypoxia effects emerge as a new frontier for studying the regulation of mammary development and lactation.
Highlights
Oxygen is critical for cellular aerobic metabolism in many higher organisms, including mammals, as it is the final electron acceptor in the electron transport chain of oxidative phosphorylation in mitochondria (Figure 1)
The glands weighed ~50% of the wild-type glands at mid-lactation; the Hypoxia-inducible factor (HIF)-1α-/- animals produced less milk than the wild-type controls, and their milk was more viscous and contained significantly elevated fat and ion contents. These data clearly indicate that, the expression of hypoxia inducible factor-1α (HIF-1α) in Mammary epithelial cells (MECs) is not required for early mammary development, it is essential for mammary secretory differentiation, milk production, and lipid secretion, implying a role for hypoxia in these physiological processes
We recently studied the effects of hypoxia on Facilitative glucose transporter (GLUT) expression in bovine MECs
Summary
Oxygen is critical for cellular aerobic metabolism in many higher organisms, including mammals, as it is the final electron acceptor in the electron transport chain of oxidative phosphorylation in mitochondria (Figure 1). The glands weighed ~50% of the wild-type glands at mid-lactation; the HIF-1α-/- animals produced less milk than the wild-type controls, and their milk was more viscous and contained significantly elevated fat and ion contents These data clearly indicate that, the expression of HIF-1α in MECs is not required for early mammary development (mainly ductal morphogenesis), it is essential for mammary secretory differentiation, milk production, and lipid secretion, implying a role for hypoxia in these physiological processes. Hypothesized that the mechanism underlying the increase in GLUT expression in MECs during the transition period from pregnancy to lactation involves hypoxia signaling through hypoxia inducible factor-1α (HIF-1α) To test this hypothesis, we recently studied the effects of hypoxia on GLUT expression in bovine MECs. Hypoxia (below 5% O2) significantly stimulated glucose uptake and GLUT1 mRNA and protein expression in bovine MECs yet decreased GLUT8 mRNA expression in these cells (Shao and Zhao, unpublished observations).
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