Neovascularization is a key regulatory process in fetal growth and development. Alterations within this process can lead to concomitant vascular and tissue abnormalities identified within lung dysplasia such as Bronchopulmonary Dysplasia (BPD). Although a significant amount of information exist regarding the pathologic progression of dysplastic lung diseases, little is known regarding the molecular mechanisms that regulate their formation. The goal of this proposal is to establish, whether the vasculature is a determinant of normal distal lung morphogenesis. We are optimally suited to determine the factors regulating this relationship based on our previous findings that: 1) the anti-angiogenic protein Endothelial-Monocyte Activating Polypeptide (EMAP) II is a director of neovascularization in the developing lung as its expression is inversely correlated to periods of vascularization, 2) introduction of recombinant EMAP II in a murine allograft model of lung development profoundly disrupts alveolar-capillary growth, 3) our fetal lung allograft model can examine neovascular and morphogenic relationships without placental barriers, 4) EphrinB2taulacZ and EphB4taulacZ transgenic mice can designate arterial versus venous vascular systems, and 5) fetal lung endothelial cells from TIE2gfp transgenic mice are readily isolated. We chose four strategies to identify the fundamental components of distal lung morphogenesis regulated by neovascularization, but may also be potential regulators of angiogenesis: 1) track arterial and venous progression in relationship to lung development, 2) characterize the signals sent by the fetal lung endothelium throughout lung development, 3) determine the impact that epithelial differentiation has on neovascularization, and 4) examine the contribution of the vasculature to epithelial mesenchymal structural organization. Thus, identifying the factors responsible for coordinating vascular formation and distal lung morphogenesis will provide insight into the determinants by which their balance can affect lung development.
