Analysis of Hepatocyte-derived sVEGFR1 in Pulmonary Arteriovenous Malformations 

PI: Andrew D. Spearman, MD
Co-Investigators: Ramani Ramchandran, PhD  and Amy Y. Pan, PhD
Medical College of Wisconsin
Amount Funded: $48,966

Children with univentricular congenital heart disease (CHD) are at risk for multiple long-term complications, including the development of pulmonary arteriovenous malformations (PAVMs). PAVMs are abnormal vascular connections in the lungs between arteries and veins. PAVMs decrease quality of life by causing hypoxia (decreased oxygen levels) and can profoundly limit physical activity. PAVMs commonly develop in children after surgical palliation for univentricular CHD, yet there are no known medical therapies to treat PAVMs. The prevailing, but unproven, hypothesis in the medical community is that the liver (hepatocytes) secretes an unidentified factor in hepatic vein blood (called hepatic factor) that regulates lung microvascular angiogenesis and homeostasis to prevent PAVMs. When univentricular palliation changes blood flow to the lungs and prevents hepatic factor from reaching the lungs, PAVMs develop. 

The identify and mechanism of hepatic factor remain unknown, which limits development of effective medical therapies to treat PAVMs. The overall objective of our research is to improve our understanding of CHD-associated PAVMs and identify hepatic factor. Our preliminary screen of patient blood samples identified a promising hepatic factor candidate – soluble vascular endothelial growth factor receptor 1 (sVEGFR1). In this proposal, our specific objective is to investigate how sVEGFR1 regulates the lung microvasculature in vitro and in vivo. We hypothesize that hepatocyte-derived sVEGFR1 regulates lung microvascular angiogenesis and loss of sVEGFR1 perfusion to the lungs causes vascular remodeling and PAVMs (Fig 1). We will test our hypothesis by using patient blood samples and cell culture techniques (Aim 1) and by manipulating mouse genetics to develop a mouse model of PAVMs (Aim 2). Improving our understanding of sVEGFR1 and creating a model of CHD-associated PAVMs are prerequisites to develop medical therapies to eliminate PAVMs in children with univentricular CHD. Eradicating PAVMs will improve oxygen saturations and quality of life in patients with univentricular CHD.