Prolonged mild hypoxia initiates a sequence of vascular and metabolic adaptations in the rat brain. Angiogenesis and the resultant increased capillary density that occurs over a 3 week time course is an important aspect of the adaptation process. The long term goals of these investigations are to understand and to be able to manipulate the molecular mechanisms responsible for microvascular remodeling in the brain. These mechanisms that allow the neurovascular unit to adapt to environmental challenges are also likely to be involved in the vascular remodeling that occurs with learning, and which may be diminished with age. These processes can have an important contribution to the pathophysiology of ischemia and other metabolic and oxidative stresses. There appear to be 2 major pathways responsible for brain angiogenesis: a hypoxia-inducible factor-1 (HIF-1a) dependent upregulation of vascular endothelial growth factor (VEGF), and a HIF-1a independent upregulation of angiopoietin-2 (Ang-2). The first specific aim of this proposal is to determine if Ang-2 expression occurs by a mechanism involving prostaglandin E2 (PGE2) production after upregulation of cyclooxygenase-2 (COX-2) activity in mice exposed to hypoxia. When hypoxic adapted animals are returned to normoxia (recovery), the subsequent capillary regression is apparently due to upregulation of Ang-2 in the absence of VEGF inducing endothelial cell apoptosis.
The second aim of this proposal is to use a binary mouse molecular genetics approach to explore the role of Ang-2 and VEGF in angiogenesis and capillary regression. The working hypothesis of these investigations is that capillary structure is greatly affected by the balance between VEGF and Ang-2. When Ang-2 is increased in the presence of VEGF then angiogenesis will occur; if Ang-2 is elevated in the absence of VEGF then the endothelial cells will undergo apoptosis.
The third aim will explore the consequences of the impaired response of HIF-1a to hypoxia and to determine if angiogenesis is thereby inhibited in aged rats; and, if the Ang-2 response is still robust, to determine whether capillary regression might be induced instead. An attempt will be made to induce HIF-1 accumulation in these older rats, through tilorone treatment to restore microvascular plasticity. ? ?
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