Sustained inhibition of experimental neointimal hyperplasia with a genetically modified herpes simplex virus

Michael A. Curi, Christopher L. Skelly, Shari L. Meyerson, Zachary K. Baldwin, Viji Balasubramanian, Sunil J. Advani, Seymour Glagov, Bernard Roizman, Ralph R. Weichselbaum, Lewis B. Schwartz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Objective: Reported herein is a potential strategy for sustained smooth muscle cell (SMC) inhibition with a virulence-attenuated herpes simplex virus (HSV). Experiments were conducted in vitro to demonstrate selective SMC cytotoxicity and in vivo to demonstrate reduced neointimal hyperplasia (NIH) in a clinically relevant animal model. Methods: In vitro: Cultured human umbilical artery smooth muscle cells (UASMC) and venous endothelial cells (HUVEC) were exposed to varying multiplicities of infection (MOI) of a γ134. 5-deleted HSV-1 virus (R849). Cell survival was assessed at 48 and 72 hours with a colorimetric MTT viability assay. In vivo: New Zealand White rabbit external jugular veins (n = 21) were exposed to R849 (2.5 × 106 pfu/mL) or culture medium at 110 to 120 mm Hg for 10 minutes, then fashioned as vein patches on carotid arteries. Carotid arteries were ligated distally to decrease blood flow and stimulate a hyperplastic response (ultra-low shear stress model). After 2, 4, 12, and 24 weeks, patched segments were perfusion-fixed with glutaraldehyde and morphometrically examined for NIH formation. Results: In vitro: At 48 hours, R849 exhibited preferential cytotoxicity to UASMC compared with HUVEC, with 11% ± 10% of UASMCs and 49% ± 8% of HUVECs surviving after infection with MOI = 25 (P < .05). Higher MOI resulted in poor survival of both cell lines. In vivo: Blood flow was similarly reduced in all animals both at surgery (0.9 ± 0.1 mL/min vs 1.6 ± 0.3 mL/min) and at harvest (2.7 ± 0.4 mL/min vs 2.5 ± 0.5 mL/min). R849-infected patches exhibited markedly less NIH than control patches did at 2 weeks (162 ± 14 μm vs 49 ± 6 μm; P < .05), 4 weeks (190 ± 27 μm vs 67 ± 8 μm; P < .05), and 12 weeks (233 ± 18 μm 113 ± 2 μm; P < .05). Conclusion: The virulence-attenuated HSV strain R849 demonstrates selective cytotoxicity for SMC and is capable of sustained inhibition of NIH in an experimental model of vein graft failure.

Original languageEnglish (US)
Pages (from-to)1294-1300
Number of pages7
JournalJournal of Vascular Surgery
Volume37
Issue number6
DOIs
StatePublished - Jun 2003

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

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