The proposed studies represent a continuing effort to understand better the mechanisms involved in growth regulation of the vascular system. The studies focus on a metabolic theory of blood vessel development and the mechanisms which cause blood vessels to proliferate when the metabolic requirements of the tissue cells exceed the perfusion capabilities of the vascular system. Since our initial studies in chick embryos point to oxygen as a major control element in the growth regulation process, a major portion of the proposal examines multiple dynamic aspects of the oxygen control system. Phase include studies to determine (a) age-related changes in the sensitivity of the vasculature to growth modification by hypoxia, hyperoxia, and adenosine, (b) whether the blood vascular system grows to meet the maximum or the average oxygen needs of the tissue cells, (c) the extent to which hypoxia can initiate vasoproliferation in a nonproliferating vasculature, (d) whether adenosine has a physiological role in the development of the vasculature, and (e) the kinetics of adenosine induced growth of in vivo endothelial and smooth muscle cells. Additional studies are designed to examine critically the role of mechanical factors related to flow and vasodilation to determine the individual importance of these in the development of the vasculature in the absence of metabolic, hormonal, and nervous influences from the body. The chick embryo is used in many experiments because its cardiovascular system grows rapidly making possible to study- within days patterns of vascular growth and regression that require weeks or months in older animals. Elementary concepts and hypotheses developed in chick embryos will then be tested quantitatively. Newly developed perfusion techniques are used to provide functional estimates of vascularity, and these coupled with com-puterized morphometry, microdensitometry, fluorescence microscopy, and autoradiography techniques provide comprehensive measurements of vascular development in the proposed experiments. A long-term goal is to integrate our findings with those from other laboratories to develop a mathematical computer model of blood vessel growth and related adaptations of the microcirculation. Once armed with a better knowledge of an-giogenesis, we can hope to modify the vasculature to the benefit of mankind in disease states such as cancer, arteriosclerosis, coronary artery disease, rheumatoid arthritis, and others where control of angiogenesis may have therapeutic value.
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