The purpose of this proposal is .to understand the mechanisms of VEGF action after its administration to the CNS with respect to permeability and angiogenesis and to utilize VEGF's effects to create methods to circumvent the blood-brain barrier (BBB) with minimal invasiveness. Although VEGF and its receptors are known to be upregulated after injury, little information exists on its application to brain tissue. Experiments will attempt to explore models of VEGF as a permeability agent restricted to specific brain areas that will serve as a portal to subsequently allow intravascular administration of compounds that would never cross the BBB rapid access to neuropil. Previous attempts to disrupt the BBB have been global nature and produced random and disseminated openings; in contrast this proposal examines BBB disruption in a strictly focal manner.
Aims 1 and 2 examine VEGF angiogenic and permeability effects either after direct focal application by acute or chronic convection enhanced microinfusion (Aim 1) or indirectly using our novel method of grafting isolated clusters of VEGF-treated brain microvessels (Aim 2) to restricted areas of striatum. The spatial and temporal degree of permeability and its receptor-mediation will be examined, and in both Aims we will determine in principle, the feasibility of intravascular delivery of certain non-permeable bioactive compounds such as radiolabeled dopamine (DA), GABA, or the neurotrophic factor, GDNF. Because consistent and effective BBB circumvention is presently perceived as exceptionally difficult problem in neurobiology, the long range goals are to elucidate whether VEGF with its unique permeability, angiogenic and anti-apoptotic properties could be an important agent for molecular delivery in CNS interventional paradigms. These studies may provide impetus for the further design strategies for the circumvention of the BBB and/or the targeting of VEGF receptor mediated effects in brain injury. ? ?
