VEGF is a critical component of the highly integrated, multidirectional signaling that orchestrates lung development. Disruption of this coordinated deveIopment is reflected in neonatal lung disease with aberrant VEGF expression including congenital diaphragmatic hernia and bronchopulmonary dysplasia. VEGF activity is regulated by generation of multiple isoforms, each with unique biological properties. The temporal and spatial expression patterns suggest that each VEGF-A isoform provides distinct positional and differentiation cues required for lung vascular development. In this proposal, we will test the hypothesis that each VEGF-A isoform regulates distinct endothelial functions required for progressive pulmonary vascular specification through differential accessibility and binding to VEGF receptors, VEGFR1 and VEGFR2. We propose that early in lung development the diffusible isoforms VEGF-A120 and VEGF-AI64 induce different signal pathways that activate distinct angioblast and endothelial responses. Further, midway through lung development, the heparin-bound isoform, VEGF-A188, expressed by distal epithelial cells generates a morphogenic gradient that induces endothelial migration and alveolar-capillary alignment. Finally, we propose that during the saccular and alveolar stages, VEGF-A164 and VEGF-A188 drive endothelial specification required for microvascular development, distal airway development and formation of the air blood barrier. We will use in vitro model systems to analyze the mechanisms of cellular activation by examining isoform-specific receptor activation and associated kinase signaling pathways. Newly developed transgenic models with conditional, lung-specific expression of VEGF-A and dominant-negative soluble receptor will be used to determine the requirements for VEGF-A at each stage of development. Completion of this project will increase understanding of the mechanism of VEGF action and expand knowledge of pulmonary vascular development.
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