The vasculature is an integral part of all tissues, yet little is known about either the mechanisms that regulated blood vessel development during tissue formation, or whether tissue vascularization is critical for normal organogenesis. The lungs are one of the most vascularized tissues, and the intimate relationship between airways and lung blood vessels suggests there may be reciprocal inductive interactions that coordinate their development. Despite the importance of the vasculature is a critical functional component of the mature lungs, the molecular mechanisms that regulate vessel development, and in particular how it is co-ordinated with airway development, are unknown. The goal of this proposal is to elucidate the molecular mechanisms of lung vessel formation and to determine the relationship between vessel and airway development. Our hypothesis is that lung vascular development is regulated by angiogenic growth factors, some of which may be produced by epithelium, and that paracrine interactions may serve to coordinate the development of airways and blood vessels. In addition, the development of vessels may be critical for the continuing development of epithelium, and this feedback mechanism would also serve to ensure the concomitant development of the two systems. We hypothesize that the families of Vascular Endothelial Growth Factor (VEGF) and their receptors play important roles in the development of the lung vasculature, due to their known activity on endothelial cell development and their temporal and spatial expression in the mouse embryonic lungs. To elucidate the function of these molecules, we will inhibit their activity either by targeted gene inactivation in vivo, or by functional studies in a model of lung development, lung renal capsule grafts. The latter is a novel model of lung morphogenesis developed in our laboratory that mirrors lung development in utero, and is readily accessible to experimental manipulation. Studying the development of the lung vasculature not only addresses questions on fundamental developmental processes, but may also provide insights into pathogenesis of, and therapeutic targets for, lung diseases in which normal vascular development is a component. These may include developmental diseases such as vascular malformations, pulmonary capillary atresia, pulmonary hypoplasia, and bronchopulmonary dysplasia, as well as acquired diseases such as cancer, fibrosis and abnormal lung repair following injury.
