Abstract 681: Enhanced Notch3 Signaling Contributes to Pulmonary Emphysema in a Murine Model of Marfan Syndrome

Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in fibrillin-1 gene. Pulmonary emphysema is one of the most common manifestations in MFS. However, the pathogenesis and molecular mechanism of pulmonary emphysema in MFS patients is underexplored. Notch signaling is essential for lung development. It has been shown that constitutive Notch3 activation inhibited the differentiation of distal lung progenitors into alveolar cells. Upregulation of Notch3 promoted endothelial cell death. As our objective, we investigated whether Notch3 signaling plays a role in pulmonary emphysema in MFS. By using a murine model of MFS, mgR/mgR mice, we found the pulmonary emphysematous-appearing alveolar patterns in the lung of mgR/mgR mice by Verhoeff-Van Gieson connective tissue staining and H&E staining. Lungs in mgR/mgR mice had decreased septation in terminal alveoli compared to wild type controls. Western blot analysis demonstrated that Notch3 levels were increased in the lung of mgR/mgR mice compared to wild type controls. This is associated with decreased expression of vascular endothelia growth factor (VEGF) and increased matrix metalloproteinase (MMP) -2 and MMP-9 production in the lung of mgR/mgR mice. To confirm that the increased Notch3 signaling in mgR/mgR mice were responsible to structure alternations in the lung of mgR/mgR mice, mice were treated with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglucine t-butyl ester (DAPT), a γ -secretase inhibitor of Notch signaling. DAPT treatment was able to restore the normal lung structure in mice with MFS. This study indicates that Notch3 crosstalk with VEGF signaling pathways in the lung contribute to pulmonary emphysema in mgR/mgR mice. The results may have the potential to lead to novel strategies to prevent and treat pulmonary manifestations in patients with MFS.