In vivo studies of cerebral angiogenesis and oxygenation

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DESCRIPTION (provided by applicant): There are many clinical conditions where the brain may be damaged from chronic hypoxia including ischemia, pulmonary disorders, SIDS, anemia, dialysis, high altitude cerebral edema and Parkinson's disease. If chronic hypoxia does cause brain damage, it follows that the adaptation of the brain to chronic hypoxia is incomplete, and may be improved through induction of angiogenesis. Recent work indicates that the brain is capable of adaptation to low oxygen through angiogenesis. There is strong evidence that HIF-1alpha is a major regulatory factor in this process. We have assembled a multidisciplinary program using our unique combination of tools (including molecular biological methods, near-infrared spectroscopy, NMR and electron paramagnetic resonance) to determine the impact of tissue hypoxia on HIF-1alpha in normal and ischemic brain, and to determine the temporal link between the upregulation of HIF-1alpha and changes in brain tissue oxygenation and angiogenesis. Cerebral oxygenation is defined as the mean cerebral hemoglobin saturation (SmcO2) measured using near-infrared (NIR) spectroscopy, and the tissue pO2 (PtO2) measured using electron paramagnetic resonance (EPR) spectroscopy. In Aim 1 we study the link between HIF-1alpha stabilization and PtO2. Aim 2 will study the response of the brain to chronic hypoxia, and to the re-supply of oxygen. This includes the time-course of increased and decreased HIF-1alpha, the time-course of angiogenesis and angioregression (measured using morphometrics and cerebral blood volume where CBV is measured with quantitative NIR spectroscopy and with steady-state contrast enhanced NMR imaging), and the changes in oxygenation. Aim 3 following a similar protocol, will study chronic low flow ischemia. We will determine if HIF-1alpha is upregulated, the time-course of angiogenesis, and whether cerebral oxygenation shows complete recovery. Aim 4 will determine if the Genzyme adenovirus, containing a non-oxygen responsive HIF-1alpha construct, will result in increased HIF-1alpha protein and increased vascular density. These studies will improve our understanding of the link between angiogenesis, HIF-1alpha upregulation and oxygenation in brain, and will lay the groundwork for manipulation of angiogenesis to improve outcome from chronic hypoxia or ischemia.