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<0.05), and HIf1α (2.3 fold, p=0.01) which was associated with increased Ki-67 expression ( 1.5fold, p<0.05). In banded animals, proliferation localized to the intima (7.7% vs 3.2% positive Ki-67 cells, p<0.05) at early timepoints while adventitial proliferation (7.9% vs 3.9% positive Ki-67 cells; P<0.05) was more prominent at later timepoints.
In addition to growth factor signaling, TGFβ1 and AGTR1 expression was elevated (3.7 and 4.0fold, respectively; p<0.05 ). TGFβ1 stimulated PV endothelial cells underwent EndMT with upregulation of Snail ( 2.5fold, p=0.001 and Twist (1.4fold, p=0.07). In banded animals, intimal lesions cells co-expressed CD31 and α-SMA, and there was upregulation of Snail and Twist expression in banded animals compared to shams ( 4.7fold and 2.7fold, respectively; p<0.05), suggesting a role for EndMT.
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.
Author Disclosures: R.D. Vanderlaan: None. Y. Fu: None. J. Zhu: None. R. Montgomery: None. H. Ide: None. M. Lo Rito: None. J. Maynes: None. J. Coles: None. C.A. Caldarone: None.
- © 2016 by American Heart Association, Inc.