Kewley, Emily Margaret
(2010).
Systematic and local regulation of angiogenesis, and other adaptations, in response to hypoxia.
University of Birmingham.
Ph.D.
Abstract
Changes in oxygen levels, due to the environment or disease initiates a plethora of acute and chronic responses in the body to enable optimal physiological adaptation to overcome impaired oxygen delivery. Homeostatic regulation mechanisms in the cardiovascular and respiratory systems rapidly act to maintain oxygen supply to sustain normal metabolism; prolonged exposure to a low oxygen tension initiates changes in gene expression. In control of many of these responses is a transcription factor (hypoxia-inducible factor, HIF). Among other responses it induces changes in erythropoiesis, glycolysis and angiogenesis. This study primarily aimed to elucidate the conditions of hypoxia, local or systemic, which would initiate capillary growth in different tissues, and determine whether manipulation of the pathway (by HIF stabilisation) would enhance this response. A systemic response to hypoxia led to increased capillarity in the heart and diaphragm, and in both the local and systemic models changes in vascularity varied with degree of hypoxia, though manipulation of the HIF pathway had no effect. HIF upregulation under conditions of normoxia with muscle overload, also failed to show effects of manipulation of the HIF pathway. Therefore, ablation of individual enzymes controlling levels of HIF was utilised. A number of genes associated with angiogenesis and protein remodelling were upregulated, as seen with gene arrays, though histological evidence for the former was poor, suggesting a delay in gene expression and translation into downstream effects. We examined whether changes in plasma EPO expression were predictive of sickness upon ascent to altitude, and whether leukocytes could be used as a circulating indicator of HIF-mediated gene expression. EPO was enhanced in all subjects following exposure to hypoxia, and it may be one marker for AMS, but individual variation in gene responses to hypoxia suggests leukocytes may not be a viable indicator of the circulating systemic response to hypoxia. This study emphasises the complexity of the HIF pathway, highlighting the multitude of its effects both on a molecular and physiological level.
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