Investigation of hepatic factor in pulmonary arteriovenous malformations

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PROJECT SUMMARY The proposed studies in this K08 application will use innovative approaches to investigate soluble vascular endothelial growth factor receptor 1 (sVEGFR1) as a critical regulator of pulmonary microvascular remodeling and inhibitor of pulmonary arteriovenous malformation (PAVM) development. Vascular endothelial growth factor (VEGF) signaling is integral to sprouting angiogenesis and vascular homeostasis. If left unchecked, VEGF signaling can also lead to vascular instability and pathologic remodeling. Inhibiting VEGF signaling in multiple vascular beds can normalize existing AVMs, and supplemental sVEGFR1 can prevent brain AVMs. Using patient blood samples, we recently identified that sVEGFR1 is significantly elevated in hepatic vein serum and may be a potential inhibitor of PAVM formation in patients with univentricular congenital heart disease. The aims of this proposal will directly test our preliminary observation by examining patient blood samples and testing the effects of sVEGFR1 on the pulmonary microvasculature in vitro, ex vivo, and in vivo. The aims of this proposal are prerequisites to advancing the care of patients with univentricular congenital heart disease and PAVMs. These aims will also improve our understanding of pulmonary microvascular biology. The training plan in this K08 application will support my career development with two main goals. First, I will further develop expertise manipulating patient-derived and biologically relevant tissues in vitro and ex vivo to investigate lung endothelial cell gene expression, angiogenesis, and microvascular remodeling. Using molecular biology tools to modify variables in vitro and probe clinically oriented questions will allow me to achieve the objectives of this proposal and address new questions in the future as a physician-scientist. Second, I will acquire new skills and experience working with transgenic animal models and innovative techniques to study the lung microvasculature. The ability to adeptly use modern transgenic animal models, as well as leverage clinical skills to modify animal physiology, will position me to independently investigate clinical problems. Experience with advanced experimental techniques, such as precision cut lung slices, isolated lung perfusion, and next-generation sequencing (RNA-seq and single cell RNA-seq), will allow me to test hypotheses with innovative scientific approaches. Finally, as a physician-scientist these skills will position me well to collaborate with investigators locally and outside my institution to advance team science.