This proposal concentrates on two major aspects of the microcirculation: (1) regulation of blood vessel growth, and (2) function of the lymphatic system. Strong support now exists for the metabolic theory of angiogenesis. Yet we know little about the feedback mechanisms that increase vascularity when the metabolic requirements of the tissue cells exceed the perfusion capabilities of the blood vessels. I have developed a whole body perfusion technique in the chick embryo which makes it possible to estimate vascularity rapidly. The method is based on measurements of structural vascular resistance, i.e., the resistance of the maximally dilated vasculature. The advantage of the chick embryo is that its cardiovascular system grows rapidly, which makes it possible to study within days patterns of vascular growth and regression requiring weeks to months in older animals. Exposure to hypoxia increases vascularity in the chick embryo, causing the blood vascular system to grow to meet the maximum oxygen needs of the tissue cells. Adenosine may mediate to some extent this angiogenesis induced by hypoxia. The proposed new studies on vascularity focus especially on critical aspects of the oxygen control system, e.g., the kinetics of hypoxia induced endothelial cell growth; oscillation in the oxygen control system; the relative growth sensitivities of capillaries, arteries, and veins to hypoxia; the possible roles, of adenosine and lactate as mediators of hypoxia induced angiogenesis, and so forth. One of my long-term goals is to develop a mathematical systems analysis of blood vessel growth to understand better the quantitative aspects of the angiogenesis process, and its relationship to the tissue environment. Possibly this will lead to new treatments for diseases where controlling angiogenesis may have therapeutic value such as cancer, myocardial infarction, arteriosclerosis, and many more. Additional studies, also related to the tissue environment, focus on mechanisms of lymph modification by lymph nodes in conscious sheep, long-term adaptation of the lymphatic smooth muscle pump to increases pumping requirements, and how the lymphatic pump might generate negative pressure in the free tissue fluid of some tissues. These studies are part of a long-term effort to establish new quantitative data for an overall systems analysis of microvascular fluid dynamics, which will make it possible to better understand the mechanisms of edema formation as well as other concepts related to fluid equilibria at the capillary level.
