The long term goal of this research is to understand how the growth of blood vessels in the brain is controlled. Endothelium is a vital cellular component of the nervous system, is the conduit for circulation and exchange of metabolites, is the major interface of the blood-brain barrier, and has important chemical and regulatory functions. The cellular and molecular mechanisms which regulate the growth of brain endothelium during normal angiogenesis are uncertain. These mechanisms relate to congenital arteriovenous malformations, which arise from errors during brain angiogenesis, and to brain hemangioblastomas, in which proliferation of endothelial-like cells is uncontrolled. In addition, insufficient capillary growth in the retina of premature infants may initiate retrolental fibroplasia and blindness. Finally, brain tumors depend upon angiogenesis from brain endothelium for their growth and survival and might be controlled by inhibiting these mechanisms. The model selected for brain angiogenesis is the transparent albino Xenopus laevis tadpole. The structure of individual capillaries on the surface of the optic tectum can be resolved by light microscopy in vivo. The first specific aim is to chart the growth of the network of blood vessels in individual tadpoles from stage 43 with only a few capillaries through the major 4-6 week period of angiogenesis as the optic tectum grows about 10-fold in surface area. Second, quantitative determinations will be made for density of capillary sprouts, intratectal vascular branches, and capillary lengths per surface area. Third, angiogenic growth factors and inhibitors will be injected into the blood, ventricular fluid, and pial spaces with micropipettes to alter the growth of tectal blood vessels. Fourth, antisera and monoclonal antibodies will be produced against Xenopus endothelium as developmental markers. A fifth aim is to culture capillary endothelium, macrophages, and pericytes from the same albino strain of Xenopus and to test angiogenic responses in vitro and interactions of marked cells with brain angiogenesis in vivo.
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