Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model

J. M. Waugh, E. Yuksel, J. Li, M. D. Kuo, M. Kattash, Romil Saxena, R. Geske, S. N. Thung, S. M. Shenaq, S. L C Wooc

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52 ± 3.72% of available lumen, while viral controls reached 86.85 ± 2.82% thrombotic occlusion; in contrast, Adv/RSV- THM reduced thrombosis to 28.61 ± 3.31% of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.

Original languageEnglish (US)
Pages (from-to)84-92
Number of pages9
JournalCirculation Research
Volume84
Issue number1
StatePublished - Jan 8 1999
Externally publishedYes

Fingerprint

Thrombomodulin
Thrombosis
Rabbits
Protein C
Hemostasis
Granulocytes
Thrombin
Anticoagulants
Endothelial Cells
Arteries
Macrophages
Wounds and Injuries

Keywords

  • Adenovirus
  • Gene therapy
  • Protein C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Waugh, J. M., Yuksel, E., Li, J., Kuo, M. D., Kattash, M., Saxena, R., ... Wooc, S. L. C. (1999). Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. Circulation Research, 84(1), 84-92.

Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. / Waugh, J. M.; Yuksel, E.; Li, J.; Kuo, M. D.; Kattash, M.; Saxena, Romil; Geske, R.; Thung, S. N.; Shenaq, S. M.; Wooc, S. L C.

In: Circulation Research, Vol. 84, No. 1, 08.01.1999, p. 84-92.

Research output: Contribution to journalArticle

Waugh, JM, Yuksel, E, Li, J, Kuo, MD, Kattash, M, Saxena, R, Geske, R, Thung, SN, Shenaq, SM & Wooc, SLC 1999, 'Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model', Circulation Research, vol. 84, no. 1, pp. 84-92.
Waugh, J. M. ; Yuksel, E. ; Li, J. ; Kuo, M. D. ; Kattash, M. ; Saxena, Romil ; Geske, R. ; Thung, S. N. ; Shenaq, S. M. ; Wooc, S. L C. / Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. In: Circulation Research. 1999 ; Vol. 84, No. 1. pp. 84-92.
@article{90e2a0b8437b4bda9f46fd78d7c8305c,
title = "Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model",
abstract = "Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52 ± 3.72{\%} of available lumen, while viral controls reached 86.85 ± 2.82{\%} thrombotic occlusion; in contrast, Adv/RSV- THM reduced thrombosis to 28.61 ± 3.31{\%} of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.",
keywords = "Adenovirus, Gene therapy, Protein C",
author = "Waugh, {J. M.} and E. Yuksel and J. Li and Kuo, {M. D.} and M. Kattash and Romil Saxena and R. Geske and Thung, {S. N.} and Shenaq, {S. M.} and Wooc, {S. L C}",
year = "1999",
month = "1",
day = "8",
language = "English (US)",
volume = "84",
pages = "84--92",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model

AU - Waugh, J. M.

AU - Yuksel, E.

AU - Li, J.

AU - Kuo, M. D.

AU - Kattash, M.

AU - Saxena, Romil

AU - Geske, R.

AU - Thung, S. N.

AU - Shenaq, S. M.

AU - Wooc, S. L C

PY - 1999/1/8

Y1 - 1999/1/8

N2 - Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52 ± 3.72% of available lumen, while viral controls reached 86.85 ± 2.82% thrombotic occlusion; in contrast, Adv/RSV- THM reduced thrombosis to 28.61 ± 3.31% of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.

AB - Endothelial thrombomodulin plays a critical role in hemostasis by binding thrombin and subsequently converting protein C to its active form, a powerful anticoagulant. Thrombomodulin thus represents a central mechanism by which patency is maintained in normal vessels. However, thrombomodulin expression decreases in perturbed endothelial cells, predisposing to thrombotic occlusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct prevented arterial thrombosis formation in all animals, while viral and nonviral controls typically developed occluding thrombi. By histological analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52 ± 3.72% of available lumen, while viral controls reached 86.85 ± 2.82% thrombotic occlusion; in contrast, Adv/RSV- THM reduced thrombosis to 28.61 ± 3.31% of lumen in cross section. No significant intima-to-media ratio was observed in the thrombomodulin group relative to controls. Local infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery, without the inflammatory damage that has limited many other adenoviral applications.

KW - Adenovirus

KW - Gene therapy

KW - Protein C

UR - http://www.scopus.com/inward/record.url?scp=0033593595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033593595&partnerID=8YFLogxK

M3 - Article

VL - 84

SP - 84

EP - 92

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 1

ER -