The vasculature is an integral part of all tissues and its patterning is specific to each tissue. The development of the vasculature has been extensively studied, and many genes that regulate the formation, proliferation, and morphogenesis of endothelial cells have been identified. However, it is not known how blood vessels develop within the context of an organ. Vascular patterning may be controlled by the local tissue environment. Tissue cells may elaborate secreted or cell surface associated molecules that direct vascular formation and patterning. Conversely, the function of the vasculature may be more than just to supply the metabolic requirement of the tissues. It is becoming increasingly evident that endothelial cells may indeed provide specific cues to direct tissue morphogenesis. My hypothesis is that there are reciprocal inductive interactions between a tissue and its vasculature during organogenesis. This is strongly suggested in the lungs by the intimate relationship between airways and blood vessels. In the mature lungs, blood vessels accompany the airways and form capillary networks surrounding the terminal gas-exchange air-sacs or alveoli. Despite the importance of the vasculature as a critical functional component of the mature lungs, the molecular mechanisms that regulate lung vessel development, and in particular how it is coordinated with airway development, are unknown. We propose that the families of Vascular Endothelial Growth Factor (VEGF) and their receptors play important roles in the coordinated development of lung airways and blood vessels, due to their known activity on endothelial cell development and their temporal and spatial expression in the mouse embryonic lungs. We have initiated a study to elucidate the function of these molecules in lung vascular development. However, to directly test the hypothesis of epithelial-endothelial interactions, a new aim is proposed to ablate in vivo either lung epithelial or endothelial cells at specific stages of lung development and determine the consequences of the absence of one cell type on the development of the other cell type. 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.
