Talk:Abnormal Development - Hypoxia
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Cite this page: Hill, M.A. (2019, August 18) Embryology Abnormal Development - Hypoxia. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Abnormal_Development_-_Hypoxia
Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period
Nature. 2014 Jan 16;505(7483):407-11. doi: 10.1038/nature12821. Epub 2013 Dec 4.
Whiteus C1, Freitas C2, Grutzendler J1.
During the neonatal period, activity-dependent neural-circuit remodelling coincides with growth and refinement of the cerebral microvasculature. Whether neural activity also influences the patterning of the vascular bed is not known. Here we show in neonatal mice, that neither reduction of sensory input through whisker trimming nor moderately increased activity by environmental enrichment affects cortical microvascular development. Unexpectedly, chronic stimulation by repetitive sounds, whisker deflection or motor activity led to a near arrest of angiogenesis in barrel, auditory and motor cortices, respectively. Chemically induced seizures also caused robust reductions in microvascular density. However, altering neural activity in adult mice did not affect the vasculature. Histological analysis and time-lapse in vivo two-photon microscopy revealed that hyperactivity did not lead to cell death or pruning of existing vessels but rather to reduced endothelial proliferation and vessel sprouting. This anti-angiogenic effect was prevented by administration of the nitric oxide synthase (NOS) inhibitor L-NAME and in mice with neuronal and inducible NOS deficiency, suggesting that excessive nitric oxide released from hyperactive interneurons and glia inhibited vessel growth. Vascular deficits persisted long after cessation of hyperstimulation, providing evidence for a critical period after which proper microvascular patterning cannot be re-established. Reduced microvascular density diminished the ability of the brain to compensate for hypoxic challenges, leading to dendritic spine loss in regions distant from capillaries. Therefore, excessive sensorimotor stimulation and repetitive neural activation during early childhood may cause lifelong deficits in microvascular reserve, which could have important consequences for brain development, function and pathology. Comment in Development: hyperactively restricting angiogenesis. [Nat Rev Neurosci. 2014]
Clinical, genetic and environmental factors associated with congenital vertebral malformations
Mol Syndromol. 2013 Feb;4(1-2):94-105. doi: 10.1159/000345329.
Giampietro PF1, Raggio CL, Blank RD, McCarty C, Broeckel U, Pickart MA.
Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an example in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations.
KEYWORDS: Congenital vertebral malformation; Hemifacial microsomia; Klippel-Feil syndrome; Maternal diabetes; Spondylocostal dysostosis; Spondylothoracic dysostosis; Thoracic insufficiency syndrome; VACTERL syndrome
Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism
PLoS Biol. 2013 Sep;11(9):e1001666. doi: 10.1371/journal.pbio.1001666. Epub 2013 Sep 24.
Breckenridge RA1, Piotrowska I, Ng KE, Ragan TJ, West JA, Kotecha S, Towers N, Bennett M, Kienesberger PC, Smolenski RT, Siddall HK, Offer JL, Mocanu MM, Yelon DM, Dyck JR, Griffin JL, Abramov AY, Gould AP, Mohun TJ.
PLoS Biol. 2013 Dec;11(12). doi:10.1371/annotation/a9a7f37a-3fa7-4f7f-8310-1339bf5a666e.
Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery.
Comment in Fine-tuning metabolic switches. [PLoS Biol. 2013]