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(Circulation. 1999;100:2018-2024.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Reduction in Vascular Lesion Formation by Hirudin Secreted From Retrovirus-Transduced Confluent Endothelial Cells on Vascular Grafts in Baboons

Anders Lundell, MD, PhD; Andrew B. Kelly, DVM; Johanna Anderson, MS; Monique Marijianowski, PhD; Jeffrey J. Rade, MD; Stephen R. Hanson, PhD; Laurence A. Harker, MD

From the Division of Hematology and Oncology and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Ga, and the Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Md (J.J.R.).

Correspondence to Laurence A. Harker, MD, Blomeyer Professor and Director, Division of Hematology and Oncology, Emory University School of Medicine, 1639 Pierce Dr, Room 1003, Atlanta, GA 30322.

Background—The hypothesis that thrombin mediates the formation of neointimal vascular lesions at sites of mechanical vascular injury has been tested in baboons by measurement of the effects of hirudin delivered by retrovirus-transduced hirudin-secreting vascular endothelial cells (ECs) lining surgically implanted arterial vascular grafts (AVGs).

Methods and Results—The antithrombotic efficacy of baboon ECs transduced with cDNA encoding hirudin was assessed in vitro and in vivo on thrombogenic segments in chronically exteriorized femoral arteriovenous (AV) shunts. Bilateral brachial AVGs lined with hirudin-transduced versus nonhirudin control ECs at confluent density were surgically implanted, and vascular lesion formations at distal graft-vessel anastomoses were compared after 30 days. Hirudin-transduced ECs secreted 20±6 ng · 10⁶ cells^-1 · 24 h^-1 (range, 14 to 24 ng · 10⁶ cells^-1 · 24 h^-1) hirudin in supernatants of static cultures. Hirudin-secreting ECs on segments of collagen-coated graft interposed in chronic AV shunts decreased the accumulation of ¹¹¹In-labeled platelets to 0.52±0.34x10⁹ platelets, compared with 0.82±0.49x10⁹ platelets in controls (P=0.03) and reduced platelet deposition in propagated thrombotic tails extending downstream from segments of vascular graft from 1.38±0.41x10⁹ platelets in controls to 0.59±0.22x10⁹ platelets (P=0.04). ECs recovered from 30-day AVG implants generated 17±9 ng · 10⁶ cells^-1 · 24 h^-1 (range, 9 to 25 ng · 10⁶ cells^-1 · 24 h^-1) hirudin. Hirudin-secreting ECs reduced neointimal lesion formation at distal graft-vessel anastomoses, ie, 1.02 mm² (range, 0.88 to 1.95 mm²) versus 1.82 mm² (range, 0.88 to 2.56 mm²) in contralateral AVGs bearing nonhirudin control ECs (P<0.01).

Conclusions—Viral vector–directed secretion of hirudin from ECs lining implanted AVGs significantly reduces the formation of thrombus and neointimal vascular lesions.

Key Words: lesion • anticoagulants • viruses • grafting

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