Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development

Susan Jung, Gudrun Boie, Helmuth-Guenther Doerr, Regina Trollmann
2017 American Journal of Physiology. Regulatory Integrative and Comparative Physiology  
Jung S, Boie G, Doerr H, Trollmann R. Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development. Perinatal hypoxia severely disrupts metabolic and somatotrophic development, as well as cerebral maturational programs. Hypoxia-inducible transcription factors (HIFs) represent the most important endogenous adaptive mechanisms to hypoxia, activating a broad spectrum of growth factors that contribute to cell survival and
more » ... y homeostasis. To analyze effects of systemic hypoxia and growth hormone (GH) therapy (rhGH) on HIF-dependent growth factors during early postnatal development, we compared protein (using ELISA) and mRNA (using quantitative RT PCR) levels of growth factors in plasma and brain between normoxic and hypoxic mice (8% O 2, 6 h; postnatal day 7, P7) at P14. Exposure to hypoxia led to reduced body weight (P Ͻ 0.001) and length (P Ͻ 0.04) compared with controls and was associated with significantly reduced plasma levels of mouse GH (P Ͻ 0.01) and IGF-1 (P Ͻ 0.01). RhGH abrogated these hypoxia-induced changes of the GH/IGF-1 axis associated with normalization of weight and length gain until P14 compared with controls. In addition, rhGH treatment increased cerebral IGF-1, IGF-2, IGFBP-2, and erythropoietin mRNA levels, resulting in significantly reduced apoptotic cell death in the hypoxic, developing mouse brain. These data indicate that rhGH may functionally restore hypoxia-induced systemic dysregulation of the GH/IGF-1 axis and induce upregulation of neuroprotective, HIFdependent growth factors in the hypoxic developing brain. insulin-like growth factors; IGF-1; IGF-2; somatotrophic axis; perinatal hypoxia; neuroprotection; cerebral apoptosis; erythropoietin; hypoxia-inducible transcription factors TISSUE HYPOXIA and ischemia during perinatal development, for example, as a consequence of utero-placental or placenta-fetal insufficiency, or maternal gestational disease (e.g., diabetes, eclampsia), as well as postnatal hypoxic complications, such as apneic spells or cardiovascular insufficiency (6, 23, 29), are well known predisposing risk factors for intermittent acute and chronic perinatal hypoxia and metabolic restriction (9, 23, 41). This may result in long-term disturbances of growth and development (e.g., fetal growth restriction, intrauterine growth retardation), as well as hypoxic-ischemic (HI) multiorgan failure, including HI brain injury.
doi:10.1152/ajpregu.00477.2016 pmid:28228417 fatcat:jompcfrsjvhrxn5jldpcbcwiam