Abstract 18643: Proliferation and Endothelial to Mesenchymal Transition Contribute to Progressive Lesions in a Surgical Model of Pulmonary Vein Stenosis

Introduction: The role of proliferation and endothelial-to-mesenchymal transition (EndMT) is poorly defined in progressive pulmonary vein stenosis (PVS). Hypothesis: Altered signaling leads to hypercellular (PVS) lesions through proliferation and EndMT, which can be modulated by losartan. Methods: We used molecular and biochemical techniques to characterize progression of PVS in banded and losartan treated piglets. Results: Our surgical model of PVS demonstrates progressive hypercellular lesions, with increasing amount of complex lesions between 3 and 7 weeks post banding (3.4% vs 34%, p=0.002). Lesions were rich in mesenchymal cells (α- SMA positive), with increased expression of fibronectin (2.6fold, p=0.05) and collagen 1A1(2.5fold, p=0.05). Banded animals had elevations in PDGFRβ (2.6fold, p=0.001), FGFR2 (3 fold, p In addition to growth factor signaling, TGFβ1 and AGTR1 expression was elevated (3.7 and 4.0fold, respectively; p Losartan ameliorates the PVS phenotype in our model and correlates with a significant reduction in complex lesions in losartan-treated banded animals compared to banded animals (11% vs 34%, p=0.01). This is accompanied by reduced expression of Twist, Snail and TGFβ1 in losartan-treated banded animals ( 2.5, 2.0 and 2.0fold,respectively, p≤0.05), but without significant reductions in Ki 67 expression. Conclusion: Proliferation and EndMT play a role in development of neointimal lesions in PVS. Losartan primarily targets the contribution of EndMT to PVS lesion development and progression.