Prolonged mild hypoxia results in an increase in brain capillary density as an integral part of the acclimatization process. There are 2 major pathways responsible for brain angiogenesis: a hypoxiainducible factor-1 (HIF-1a) dependent upregulation of vascular endothelial growth factor (VEGF), and a HIF-1a independent upregulation of cycloxygenase-2 (COX-2) and angiopoietin-2 (Ang-2). Upon return to normoxia, the capillary density returns to pre-hypoxic baseline through an angiolytic mechanism. The dynamic changes in the capillary density in response to changes in oxygen availability have led to the concept of angioplasticity which describes a balance between angiogenesis and angiolysis driven by the availability of oxygen/glucose with respect to energy demand. 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. In this proposal we seek to identify the relative roles of the components of the neurovascular unit: neurons, astrocytes and endothelial cells in the regulation of the major modulatory molecules: HIF-1, HIF-2 and COX-2 that govern angiogenesis. The primary approach will be to use specific transgenic mice to isolate the cell-type specific modulators to determine their interrelationships.
The specific aims are organized to elucidate the role of neuronal HIF-1, astrocytic HIF-2, and endothelial COX-2 in angiogenesis and, in addition, the role of endothelial COX-2 in angiolysis.
Exposure of mice to a simulated high altitude environment leads to an increase in the density of brain microvessels. In the previous years of the project we have found that the process of capillary growth is dependent on a number of molecules that act as oxygen sensors and that produce growth factors and other mediators that control the growth and death of capillaries. This new application proposes to gain a deeper understanding of the processes that control and maintain capillary density because this new information may prove useful for designing strategies for treatment of many neurodegenerative diseases such as dementia, tumors and stroke.
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