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(Stroke. 1999;30:2431-2439.)
© 1999 American Heart Association, Inc.

Original Contributions

Inhibition of Rat Vascular Smooth Muscle Cell Proliferation In Vitro and In Vivo by Recombinant Replication-Competent Herpes Simplex Virus

Shin-Ichi Miyatake, MD, PhD; Hiroyuki Yukawa, MD; Hiroki Toda, MD; Norihiro Matsuoka, MD; Rei Takahashi, MD, PhD Nobuo Hashimoto, MD, PhD

From the Department of Neurosurgery & Clinical Neuroscience (S.-I.M., H.Y., H.T., N.M., N.H.) and the Department of Pathology and Tumor Biology (R.T.), Kyoto University Graduate School of Medicine, Kyoto, Japan.

Correspondence to Shin-Ichi Miyatake, Department of Neurosurgery and Clinical Neuroscience, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan. E-mail ichi{at}kuhp.kyoto-u.ac.jp

Background and Purpose—The proliferation of vascular smooth muscle cells (VSMCs) is a common feature associated with vascular proliferative disorders such as atherosclerosis and restenosis after balloon angioplasty. We examined the antiproliferative effects of recombinant replication-competent herpes simplex virus (HSV), hrR3, to proliferative VSMCs both in vitro and in vivo.

Methods—Early passages of Sprague-Dawley rat VSMCs were infected with hrR3 at a low multiplicity of infection (0.01 to 1.0) to examine the in vitro cytotoxic activity of this recombinant HSV to VSMCs in a proliferative state. Sprague-Dawley rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. The injured carotid arteries were infected with hrR3 five days after balloon injury. Two weeks after injury, the left carotid arteries were fixed, and the areas of the neointimal and medial layers were analyzed microscopically. Because the reporter Escherichia coli lacZ gene in hrR3 is expressed only in infected cells in which the virus is actively replicating, virus replication was confirmed by X-gal staining.

Results—A morphometric analysis revealed that there were significant differences in the intima/media ratio between the HSV-treated group and mock-infected group (0.354±0.068 and 1.08±0.055, respectively). In the histological study (X-gal staining), positive X-gal staining was observed chiefly in the VSMCs in the medial layer just beneath the internal elastic lamina, indicating active viral replication.

Conclusions—Virus-mediated cytocidal therapy using recombinant HSV vector is a promising modality for the treatment of the restenosis after balloon angioplasty.

Editorial Comment

Christopher D. Kontos, MD, Guest Editor

Division of Cardiology, Duke University Medical Center, Durham, North Carolina

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