Pulmonary Vascular Tree Development, Growth & Remodling

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DESCRIPTION (provided by applicant): The pulmonary vascular tree has a unique design that optimizes the distribution of blood flow for gas exchange. Under normal conditions, its geometry is an end product of fetal development and postnatal growth. In disease, further restructuring occurs through vascular remodeling. Recent advances in molecular and cellular biology provide insights into how these three determinants influence vascular structure at the cellular level. The proposed work integrates physiologic studies with in situ cellular and molecular techniques to determine the functional significance of these factors in the whole living animal. Specific aim 1: Determine the degree of genetic control on pulmonary vascular tree growth during fetal development and how its geometry changes with postnatal growth. We will use armadillos, a unique animal that produces litters of identical offspring. By comparing the spatial distribution of blood flow within and across litters, we can quantify the genetic influence on vascular tree development and regional perfusion. We will also measure regional blood flow in growing pigs to identify patterns of blood flow redistribution. Patterns that are spatially clustered will provide evidence that postnatal growth of the pulmonary vascular tree may be locally regulated. Specific aim 2: Identify triggers of pulmonary vascular remodeling during chronic hypoxia. We will focus on the roles of mechanical wall stresses in promoting cellular proliferation and apoptosis in rat pulmonary arteries. Specific aim 3: Identify triggers of pulmonary vascular remodeling in pulmonary hypertension induced by vascular endothelial growth factor receptor-1 inhibition. We will focus on the roles of mechanical wall stresses in promoting plexiform lesions that are characteristic of primary pulmonary hypertension. The proposed work is designed to determine relationships between function, structure and genetic controls in the pulmonary circulation at the organ level. The most novel and significant aspect of the work is that cellular and molecular mechanisms will be explored in the intact animal. The findings will fill important gaps in our knowledge of pulmonary vascular development and triggers of remodeling.