Vascular Endothelial Growth Factor Prevents Endothelial-to-Mesenchymal Transition in Hypertrophy Ben M.-W. Illigens, MD, Alejandra Casar Berazaluce,

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Vascular Endothelial Growth Factor Prevents Endothelial-to-Mesenchymal Transition in Hypertrophy Ben M.-W. Illigens, MD, Alejandra Casar Berazaluce, MD, Dimitrios Poutias, BS, Robert Gasser, MD, PhD, Pedro J. del Nido, MD, Ingeborg Friehs, MD The Annals of Thoracic Surgery Volume 104, Issue 3, Pages 932-939 (September 2017) DOI: 10.1016/j.athoracsur.2017.01.112 Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Peak systolic stress and diastolic compliance. (A) Peak systolic stress was determined by weekly echocardiography over the entire observation period. Normalization of wall stress as an adaptive mechanism to compensate for increased pressure loading is preserved in vascular endothelial growth factor (VEGF)–treated hypertrophied hearts compared with untreated hearts (n = 7/group).*p < 0.05 vs VEGF-treated and control. (B) Pressure-volume curves were obtained on arrested isolated perfused hearts. Passive stiffness of the myocardium, determined in arrested hearts, is significantly higher in untreated hypertrophied hearts corresponding with a higher amount of collagen deposition in the extracellular matrix (n = 7/group). Data are shown as mean ± SD (range bars). *p < 0.05 vs VEGF-treated and control. The Annals of Thoracic Surgery 2017 104, 932-939DOI: (10.1016/j.athoracsur.2017.01.112) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Myocardial fibrosis determined by hydroxyproline assay. (A) Total amount of collagen is significantly increased in untreated hypertrophied hearts compared with vascular endothelial growth factor (VEGF)-treated and control hearts (n = 7/group). *p < 0.05. (B) Soluble collagen is significantly increased in untreated hypertrophied hearts compared with VEGF-treated and control hearts (n = 7/group). *p < 0.05. (C) Cross-linked collagen is significantly increased in untreated hypertrophied hearts compared with VEGF-treated and control hearts (n = 7/group). *p < 0.05. The Annals of Thoracic Surgery 2017 104, 932-939DOI: (10.1016/j.athoracsur.2017.01.112) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Histologic assessment of fibrosis. (A) As indicated by the representative histologic sections stained with Masson trichrome, collagen deposition (blue) is significantly higher in untreated hypertrophied hearts than in vascular endothelial growth factor (VEGF)-treated and control hearts (n = 7/group; p = 0.001). (10× magnification) (B) Total amount of collagen was analyzed by light microscopy and summary of data is depicted here (n = 7/group). *p < 0.05 vs VEGF-treated and control. The Annals of Thoracic Surgery 2017 104, 932-939DOI: (10.1016/j.athoracsur.2017.01.112) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Endothelial-to-mesenchymal transition (EndMT). (A) Representative immunohistochemical sections of EndMT in untreated hypertrophied hearts and vascular endothelial growth factor (VEGF)-treated hypertrophied hearts are shown. EndMT is identified by double-labeling of cells with cluster of differentiation (CD) 31, an endothelial cell marker in red, and fibroblast-specific protein 1 (FSP-1), a fibroblast marker in green. (B) Data summary shows cells undergoing EndMT (cells merged for CD31 and FSP-1) expressed per total number of CD31-positive cells. There are significantly fewer endothelial cells undergoing EndMT in VEGF-treated hypertrophied hearts compared with control hearts compared with untreated hypertrophied hearts (n = 4/group; p = 0.001 VEGF-treated and control vs untreated hypertrophy). (C) Representative immunohistochemical sections of EndMT in untreated hypertrophied hearts and VEGF-treated hypertrophied hearts are shown. EndMT is identified by double-labeling nuclei of CD31-positive cells in red with phosphorylated (p)SMAD2/3 in green (indicated by white arrows). (D) Data summary shows cells undergoing EndMT (CD31-positive cells with merged nuclei) expressed per total number of CD31-positive cells. These results support the extent of EndMT (n = 4/group; p = 0.001). The Annals of Thoracic Surgery 2017 104, 932-939DOI: (10.1016/j.athoracsur.2017.01.112) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 Transforming growth factor-β (TGF-β) pathway activation by quantitative real-time polymerase chain reaction: TGF-β and SMAD2 are significantly upregulated in untreated hypertrophied hearts, which coincides with EndMT. Data are expressed as mean fold-change ± SD from control (n = 6/group). *p = 0.01. (VEGF = vascular endothelial growth factor.) The Annals of Thoracic Surgery 2017 104, 932-939DOI: (10.1016/j.athoracsur.2017.01.112) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions