Inhibition of N-cadherin retards smooth muscle cell migration and intimal thickening via induction of apoptosis Cressida A. Lyon, PhD, Evgenia Koutsouki,

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Inhibition of N-cadherin retards smooth muscle cell migration and intimal thickening via induction of apoptosis Cressida A. Lyon, PhD, Evgenia Koutsouki, PhD, Concepcion M. Aguilera, PhD, Orest W. Blaschuk, PhD, Sarah Jane George, PhD Journal of Vascular Surgery Volume 52, Issue 5, Pages 1301-1309 (November 2010) DOI: 10.1016/j.jvs.2010.05.096 Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 1 Inhibition of N-cadherin reduces vascular smooth muscle cell (VSMC) migration. A, Representative images of VSMCs 24 hours after wounding and culture in the presence or absence of 1 mg/mL of the pan-cadherin antagonist (CHAVC) or control peptide (CHGVC). Quantification of VSMC migration (expressed as a percentage of the distance migrated in the presence of the control). * Indicates significant difference from control, n = 4. B, VSMC migration was measured 24 hours after wounding and treatment with 1 mg/mL N-cadherin-specific antagonist or control (CHAVDIC or CHGVDIC), 10 μg/mL immunoglobulin G (IgG) or anti-N-cadherin neutralizing antibody, or infection with RAd LacZ or dn-N-cad. * Indicates significant difference from control, † indicates significant difference from IgG control, and $ indicates significant difference from uninfected and LacZ controls, n = 3. Journal of Vascular Surgery 2010 52, 1301-1309DOI: (10.1016/j.jvs.2010.05.096) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 2 Apoptosis occurs because of N-cadherin inhibition. A and B, Representative images to show apoptotic vascular smooth muscle cells (VSMCs) detected by in situ end labelling (ISEL) (brown) at wound edge after treatment with 10 μg/mL immunoglobulin G (IgG: A) or anti-N-cadherin neutralizing antibody (B). Nuclei are stained blue with hematoxylin. ISEL-positive cells are brown. Scale bar represents 30 μm. C, Percentage of apoptotic VSMCs (ISEL positive) at wound edge 24 hours after wounding and treatment with 10 μg/mL immunoglobulin G (IgG) or anti-N-cadherin neutralizing antibody, or infection with RAd LacZ or dn-N-cad. * Indicates significant difference from IgG control, † indicates significant difference from uninfected and LacZ controls, n = 3. D, Percentage of apoptotic VSMCs (ISEL positive) at wound edge 24 hours after wounding and treatment with 1 mg/mL pan-cadherin (CHAVC) or N-cadherin-specific antagonists (CHAVDIC) or controls (CHGVC or CHGVDIC). * Indicates significant difference from pan-cadherin control (CHGVC), † indicates significant difference from N-cadherin-specific control (CHGVDIC), n = 3. E, Percentage of apoptotic VSMCs (ISEL positive) at wound edge 24 hours after wounding. * Indicates significant difference from pan-cadherin control (CHGVC), † indicates significant difference from pan-cadherin antagonist (CHAVC) alone, $ indicates a significant difference from IgG, and # indicates a significant difference from anti-N-cadherin-neutralizing antibody alone, n = 3. Journal of Vascular Surgery 2010 52, 1301-1309DOI: (10.1016/j.jvs.2010.05.096) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 3 pAkt is reduced by N-cadherin inhibition. Representative images and quantification of pAkt in vascular smooth muscle cells (VSMCs) at the wound edge 24 hours after wounding and treating with anti-N-cadherin neutralizing antibody or nonimmune immunoglobulin control. Scale bar applies to both panels and represents 30 μm. * Indicates a significant difference from IgG control, n = 3. Journal of Vascular Surgery 2010 52, 1301-1309DOI: (10.1016/j.jvs.2010.05.096) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 4 Intimal thickening is reduced by dn-N-cadherin. Representative detection of β-galactosidase protein by X-gal staining (blue) at 3 days (A) and 7 days (B). Scale bar in A represents 50 μm and applies to panels A and B. Inset shows media X-gal staining. Representative ISEL detection of apoptotic cells (brown) and nuclei are stained blue with hematoxylin in RAd LacZ-infected control segment (C) and RAd dn-N-cad-infected segment (D) at 7 days. Scale bar in C represents 20 μm and applies to panels C-D. Representative elastin van Gieson staining of RAd LacZ-infected control segments (E-G) and RAd dn-N-cad-infected segment (H-J) at 7 (E and H), 10 (F and I), and 14 (G and J) days. Scale bar represents 50 μm. (K) Quantification of intimal area in RAd LacZ and RAd dn-N-cad-infected vein segments. * Indicates a significant difference from RAd LacZ control, n = 6. Journal of Vascular Surgery 2010 52, 1301-1309DOI: (10.1016/j.jvs.2010.05.096) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 5 Endothelial cell coverage is increased by dn-N-cadherin. Quantification of endothelial cell coverage assessed by QBend10 immunohistochemistry. *Indicates a significant difference from RAd LacZ control, n = 6. Representative images of QBend10 staining of human saphenous vein organ cultures 14 days after infection with RAd LacZ or RAd dn-N-cadherin. Brown color indicates endothelial cells and nuclei are stained blue with hematoxylin. Scale bars represent 20 μm. Journal of Vascular Surgery 2010 52, 1301-1309DOI: (10.1016/j.jvs.2010.05.096) Copyright © 2010 Society for Vascular Surgery Terms and Conditions

Fig 6 N-cadherin inhibition reduces endothelial cell apoptosis. Human saphenous vein endothelial cells were cultured in serum-free media for 24 hours to induce apoptosis in the presence of anti-N-cadherin neutralizing antibody or nonimmune immunoglobulin control, N-cadherin-specific antagonist (CHAVDIC), or control peptide (CHGVDIC). Apoptosis was quantified by in situ end labelling (ISEL) (A). Human saphenous vein endothelial cell migration was assessed 24 hours after wounding (B), and proliferation was assessed by BrdU incorporation (C). * Indicates a significant difference from the non-immune IgG control, † indicates a significant difference from control peptide (CHGVDIC), n = 3. Journal of Vascular Surgery 2010 52, 1301-1309DOI: (10.1016/j.jvs.2010.05.096) Copyright © 2010 Society for Vascular Surgery Terms and Conditions