Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety Stephan.

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Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety Stephan Winnik, Christine Lohmann, Giovanni Siciliani, Tobias von Lukowicz, Kira Kuschnerus, Nicolle Kraenkel, Chad E. Brokopp, Frank Enseleit, Stephan Michels, Frank Ruschitzka, Thomas F. Lüscher, Christian M. Matter International Journal of Cardiology Volume 168, Issue 3, Pages 2453-2461 (October 2013) DOI: 10.1016/j.ijcard.2013.03.010 Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 Systemic VEGF-R inhibition increases atherosclerotic plaque burden: 8-week-old male ApoE-/- mice on a high cholesterol diet (1.25% w/w) were exposed to the pan-VEGF receptor [VEGF-R] inhibitor PTK787 (50mg/kg/d, gavage) or placebo for 10weeks before aortae were explanted and atherosclerotic lesions assessed. (A) Thoraco-abdominal aortae en face, oil red o staining (purple), scale bars=1mm. n=10 per group. (B, C) Photomicrographs of aortic arches, longitudinal sections, oil red o- [ORO-] (B) and CD68- (C) staining (both purple), scale bars=1mm, n=5 per group. *p<0.05, **p<0.01; graphs show interquartile ranges, whiskers indicate minima and maxima. International Journal of Cardiology 2013 168, 2453-2461DOI: (10.1016/j.ijcard.2013.03.010) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 Systemic VEGF-R inhibition does not alter features of plaque vulnerability in experimental atherosclerosis: (A) Photomicrographs of longitudinal sections of aortic arches from ApoE-/- mice treated with PTK787 or placebo; Elastic van Gieson’s [EvG] stain, top: scale bars=1mm, dotted line indicates magnified sectors below, bottom: scale bars=130μm, dotted straight lines indicate necrotic core diameters, dotted curved lines indicate acellular necrotic core area, arrows indicate fibrous cap thickness. (B) Quantifications of necrotic core diameter, acellular necrotic core area, and fibrous cap thickness, n=5 per group, graphs show interquartile ranges, whiskers indicate minima and maxima. International Journal of Cardiology 2013 168, 2453-2461DOI: (10.1016/j.ijcard.2013.03.010) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Systemic VEGF-R inhibition does not affect the number of plaque-resident endothelial cells: Micrographs of longitudinal sections of aortic arches from ApoE-/- mice treated with PTK787 or placebo are displayed. (A) CD31 staining (purple). Arrows indicate nucleated CD31-positive signals (B) Von Willebrand Factor [vWF] staining (green), nuclei (blue). Arrows indicate nucleated vWF-positive signals. vWF-positive area was normalized to the number of nuclei. Scale bars=100μm, n=5 per group, graphs show interquartile ranges, whiskers indicate minima and maxima. International Journal of Cardiology 2013 168, 2453-2461DOI: (10.1016/j.ijcard.2013.03.010) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 4 Systemic VEGF-R inhibition attenuates proliferation and endothelial eNOS expression (trend) in aortic atherosclerotic lesions: Immunofluorescent stainings of aortic arches (longitudinal sections) from ApoE-/- mice treated with PTK787 or placebo are displayed. (A) Proliferating Cell Nuclear Antigen [PCNA] staining (green), scale bars=50μm (B) endothelial nitric oxide synthase [eNOS] staining (green), nuclei (blue), scale bars=1mm (top) and 350μm (bottom). *p<0.05, graphs show interquartile ranges, whiskers indicate minima and maxima; n=5 per group. International Journal of Cardiology 2013 168, 2453-2461DOI: (10.1016/j.ijcard.2013.03.010) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 5 VEGF-R inhibition impairs eNOS function in human aortic endothelial cells: Human aortic endothelial cells [HAEC] were incubated with the indicated doses of PTK787 or vehicle for 24h and subjected to biochemical analyses. (A) Expression of endothelial nitric oxide synthase (eNOS), in-cell western analyses. (B) Expression of monomeric and dimeric eNOS, non-denaturing in-gel western analyses, hydrogen peroxide [H2O2] served as positive control. (C) Nitric oxide [NO] release, diaminofluorescein (DAF-2) conversion. (D) Intracellular superoxide generation, electron spin resonance [ESR] spectroscopy. (E) Endothelial proliferation, bromodeoxyuridine [BrdU] incorporation. (F) Cytotoxicity, lactate dehydrogenase release into the supernatant. (G–I) Representative ESR spectra of intracellular superoxide generation. *p<0.05, **p<0.01, ***p<0.001. International Journal of Cardiology 2013 168, 2453-2461DOI: (10.1016/j.ijcard.2013.03.010) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 6 VEGF-R inhibition increases mitochondrial superoxide generation in human aortic endothelial cells: Human aortic endothelial cells [HAEC] were incubated with the indicated doses of PTK787 or vehicle for 24h and subjected to biochemical analyses. (A) Mitochondrial superoxide (red) generation, representative micrographs of HAEC after incubation with a fluorogenic mitochondrial-specific superoxide indicator (MitoSOX™, 5μM, 10min), nuclei (blue), left panel: representative magnification of a single cell. (B) Quantification of mitochondrial superoxide generation. (C) Relative comparison of total intracellular superoxide (dotted line) and mitochondrial superoxide generation (solid line). (D) NADPH oxidase activity, relative turnover of extracted NADPH. Scale bars=50μm, ***p<0.001. International Journal of Cardiology 2013 168, 2453-2461DOI: (10.1016/j.ijcard.2013.03.010) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions