Abstract 12567: A Novel Mouse Model Replicates Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

Abstract

Background: 1 in 5,000 people worldwide present with Hereditary Hemorrhagic Telangiectasia (HHT), a vascular disorder that is most frequently caused by mono-allelic loss of function either of the gene ALK1, or ENG . Up to 50% of patients with HHT develop Pulmonary Arteriovenous Malformations (pAVMs), abnormal connections between arteries and veins. Health consequences include stroke, or rupture of the pAVM with life threatening bleedings. How pAVMs develop is unknown and there is no cure. Aims: We here aim at generating the first mouse model with pAVMs in HHT to address how pAVMs arise and grow, and to enable preclinical drug testing. Our goal is to produce the characteristic sac-like appearance of pAVMs in random locations of the lung by replicating probable underlying genetic events of HHT patients. Methods and Results: pAVMs occur in a focal fashion, despite a systemic mono-allelic loss of function in either one of the genes ALK1 or ENG in HHT. Recently, somatic mutations causing a local bi-allelic loss of ALK1 or ENG were identified in skin vascular abnormalities of HHT patients, most likely in clonally expanding endothelial cells (ECs). To recapitulate this locally confined complete loss of function of Alk1 in the mouse lung, we generated a tamoxifen-inducible (TM) Cre-lox mouse in which bi-allelic deletion of Alk1 can be induced only in a subset of ECs of mouse pulmonary capillaries. TM was administered in P11 or P13 old mice. 5-6 days post-injection, focal sac-like structures of the pulmonary arteries with potential connections to veins were visible in random locations of the mouse lungs of Alk1 mutants, but not control lungs. Conclusion: Bi-allelic deletion of Alk1 in ECs of mouse pulmonary general capillaries closely mimics a local loss of function somatic mutation in the single functional allele of ALK1 , as uncovered in vascular abnormalities of patients with HHT. Our novel mouse model is the first to faithfully recapitulate the focal and sporadic occurrence of pAVM-like structures seen in HHT patients. This will now enable us to identify molecular drivers of pAVM formation and test therapeutics to prevent or halt pAVM development.