Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis

Chengwei Shi, Anand Patel, Dorothy Zhang, Hong Wang, Peter Carmeliet, Guy L. Reed, Mu En Lee, Edgar Haber, Nicholas E.S. Sibinga

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Recent studies of mice that lack plasminogen have identified a critical role for this zymogen in arterial remodeling. To permit the use of these (and other) genetically modified mice in the analysis of venous injury, we developed a model in which a patch cut from the external jugular vein of a mouse is grafted to repair a surgically created defect in its carotid artery. In wild-type mice, the venous graft showed initial endothelial denudation and formation of a neointima that progressively and reproducibly expanded in a manner analogous to human vein graft disease, albeit at an accelerated pace. This neointima occupied 37 ± 4.6% of the vessel lumen at day 7 and 66 ± 5.7% at day 20. The proliferative index of neointimal cells assessed by proliferating cell nuclear antigen staining was 50.6 ± 3.6% at day 7 and 15.2 ± 2.0% at day 20. CD45-positive leukocytes and α-actin-positive smooth muscle cells accounted for 9.5 ± 1.0% and 9.9 ± 1.1% of intimal area at day 7, respectively, with the latter increasing to 40.9 ± 2.6% at day 20. Collagen accounted for 6.8 ± 0.7% of intimal area at day 7 and 20.7 ± 1.8% at day 20. Surprisingly, even though arterial neointima formation due to electrostatic and immune-mediated injury is impaired in plasminogen -/- mice, in our study vein graft neointima formation in these mice was not significantly different from that in controls (70.9 ± 6.4 versus 65.6 ± 4.4% luminal occlusion, P=NS). Thus, plasmin proteolysis, although critical in extracellular matrix degradation and cellular migration after arterial injury, does not appear to be so important in vein graft neointima formation, perhaps because of the relative lack of structural barriers to cellular migration in the normal vein wall. This novel model of vein graft injury should be useful for further studies of differences in the response to injury of arterial and venous tissues.

Original languageEnglish (US)
Pages (from-to)883-890
Number of pages8
JournalCirculation Research
Volume84
Issue number8
StatePublished - Apr 30 1999
Externally publishedYes

Fingerprint

Neointima
Plasminogen
Veins
Pathologic Constriction
Transplants
Tunica Intima
Wounds and Injuries
Enzyme Precursors
Fibrinolysin
Jugular Veins
Proliferating Cell Nuclear Antigen
Static Electricity
Carotid Arteries
Proteolysis
Smooth Muscle Myocytes
Extracellular Matrix
Actins
Leukocytes
Collagen
Staining and Labeling

Keywords

  • Arteriosclerosis
  • Bypass surgery coronary disease
  • Gene knockout
  • Intimal hyperplasia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Shi, C., Patel, A., Zhang, D., Wang, H., Carmeliet, P., Reed, G. L., ... Sibinga, N. E. S. (1999). Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis. Circulation Research, 84(8), 883-890.

Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis. / Shi, Chengwei; Patel, Anand; Zhang, Dorothy; Wang, Hong; Carmeliet, Peter; Reed, Guy L.; Lee, Mu En; Haber, Edgar; Sibinga, Nicholas E.S.

In: Circulation Research, Vol. 84, No. 8, 30.04.1999, p. 883-890.

Research output: Contribution to journalArticle

Shi, C, Patel, A, Zhang, D, Wang, H, Carmeliet, P, Reed, GL, Lee, ME, Haber, E & Sibinga, NES 1999, 'Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis', Circulation Research, vol. 84, no. 8, pp. 883-890.
Shi C, Patel A, Zhang D, Wang H, Carmeliet P, Reed GL et al. Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis. Circulation Research. 1999 Apr 30;84(8):883-890.
Shi, Chengwei ; Patel, Anand ; Zhang, Dorothy ; Wang, Hong ; Carmeliet, Peter ; Reed, Guy L. ; Lee, Mu En ; Haber, Edgar ; Sibinga, Nicholas E.S. / Plasminogen is not required for neointima formation in a mouse model of vein graft stenosis. In: Circulation Research. 1999 ; Vol. 84, No. 8. pp. 883-890.
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abstract = "Recent studies of mice that lack plasminogen have identified a critical role for this zymogen in arterial remodeling. To permit the use of these (and other) genetically modified mice in the analysis of venous injury, we developed a model in which a patch cut from the external jugular vein of a mouse is grafted to repair a surgically created defect in its carotid artery. In wild-type mice, the venous graft showed initial endothelial denudation and formation of a neointima that progressively and reproducibly expanded in a manner analogous to human vein graft disease, albeit at an accelerated pace. This neointima occupied 37 ± 4.6{\%} of the vessel lumen at day 7 and 66 ± 5.7{\%} at day 20. The proliferative index of neointimal cells assessed by proliferating cell nuclear antigen staining was 50.6 ± 3.6{\%} at day 7 and 15.2 ± 2.0{\%} at day 20. CD45-positive leukocytes and α-actin-positive smooth muscle cells accounted for 9.5 ± 1.0{\%} and 9.9 ± 1.1{\%} of intimal area at day 7, respectively, with the latter increasing to 40.9 ± 2.6{\%} at day 20. Collagen accounted for 6.8 ± 0.7{\%} of intimal area at day 7 and 20.7 ± 1.8{\%} at day 20. Surprisingly, even though arterial neointima formation due to electrostatic and immune-mediated injury is impaired in plasminogen -/- mice, in our study vein graft neointima formation in these mice was not significantly different from that in controls (70.9 ± 6.4 versus 65.6 ± 4.4{\%} luminal occlusion, P=NS). Thus, plasmin proteolysis, although critical in extracellular matrix degradation and cellular migration after arterial injury, does not appear to be so important in vein graft neointima formation, perhaps because of the relative lack of structural barriers to cellular migration in the normal vein wall. This novel model of vein graft injury should be useful for further studies of differences in the response to injury of arterial and venous tissues.",
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AB - Recent studies of mice that lack plasminogen have identified a critical role for this zymogen in arterial remodeling. To permit the use of these (and other) genetically modified mice in the analysis of venous injury, we developed a model in which a patch cut from the external jugular vein of a mouse is grafted to repair a surgically created defect in its carotid artery. In wild-type mice, the venous graft showed initial endothelial denudation and formation of a neointima that progressively and reproducibly expanded in a manner analogous to human vein graft disease, albeit at an accelerated pace. This neointima occupied 37 ± 4.6% of the vessel lumen at day 7 and 66 ± 5.7% at day 20. The proliferative index of neointimal cells assessed by proliferating cell nuclear antigen staining was 50.6 ± 3.6% at day 7 and 15.2 ± 2.0% at day 20. CD45-positive leukocytes and α-actin-positive smooth muscle cells accounted for 9.5 ± 1.0% and 9.9 ± 1.1% of intimal area at day 7, respectively, with the latter increasing to 40.9 ± 2.6% at day 20. Collagen accounted for 6.8 ± 0.7% of intimal area at day 7 and 20.7 ± 1.8% at day 20. Surprisingly, even though arterial neointima formation due to electrostatic and immune-mediated injury is impaired in plasminogen -/- mice, in our study vein graft neointima formation in these mice was not significantly different from that in controls (70.9 ± 6.4 versus 65.6 ± 4.4% luminal occlusion, P=NS). Thus, plasmin proteolysis, although critical in extracellular matrix degradation and cellular migration after arterial injury, does not appear to be so important in vein graft neointima formation, perhaps because of the relative lack of structural barriers to cellular migration in the normal vein wall. This novel model of vein graft injury should be useful for further studies of differences in the response to injury of arterial and venous tissues.

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