Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation

A gene targeting and gene transfer study in mice

Peter Carmeliet, Lieve Moons, Roger Lijnen, Stefaan Janssens, Florea Lupu, Désiré Collen, Robert D. Gerard

Research output: Contribution to journalArticle

217 Citations (Scopus)

Abstract

Background: Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. Methods and Results: Neointima formation was evaluated in PAl-1-deficient (PAI-1(-/-)) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001±0.001 mm2 in PAI-1(+/+) and 0.016±0.008 mm2 in PAI-1(-/-) mice within 1 week after electric injury (P<.02) and 0.055±0.008 mm2 in PAI-1(+/+) and 0.126±0.006 mm2 in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001). Proliferation of smooth muscle cells was not affected by PAl-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1(-/-) smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than Mid-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1(-/-) mice were intravenously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61±8 μg/mL with 2x109 plaque-forming units (pfu) virus. Luminal stenosis was 35±13% in control AdRRS-treated (2x109 pfu) and suppressed to 5±5% in AdCMVPAI-1-treated (6x108 pfu) PAI-1(-/-) mice (P<.002). Conclusions: By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.

Original languageEnglish (US)
Pages (from-to)3180-3191
Number of pages12
JournalCirculation
Volume96
Issue number9
StatePublished - Nov 4 1997

Fingerprint

Neointima
Gene Targeting
Plasminogen Activator Inhibitor 1
Wound Healing
Genes
Blood Vessels
Wounds and Injuries
Electric Injuries
Smooth Muscle Myocytes
Human Adenoviruses
Plasminogen
Fibrinolysin
Gene Silencing

Keywords

  • Angioplasty
  • Genetics
  • Plasminogen
  • Stenosis
  • Viruses

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Carmeliet, P., Moons, L., Lijnen, R., Janssens, S., Lupu, F., Collen, D., & Gerard, R. D. (1997). Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: A gene targeting and gene transfer study in mice. Circulation, 96(9), 3180-3191.

Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation : A gene targeting and gene transfer study in mice. / Carmeliet, Peter; Moons, Lieve; Lijnen, Roger; Janssens, Stefaan; Lupu, Florea; Collen, Désiré; Gerard, Robert D.

In: Circulation, Vol. 96, No. 9, 04.11.1997, p. 3180-3191.

Research output: Contribution to journalArticle

Carmeliet, P, Moons, L, Lijnen, R, Janssens, S, Lupu, F, Collen, D & Gerard, RD 1997, 'Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: A gene targeting and gene transfer study in mice', Circulation, vol. 96, no. 9, pp. 3180-3191.
Carmeliet, Peter ; Moons, Lieve ; Lijnen, Roger ; Janssens, Stefaan ; Lupu, Florea ; Collen, Désiré ; Gerard, Robert D. / Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation : A gene targeting and gene transfer study in mice. In: Circulation. 1997 ; Vol. 96, No. 9. pp. 3180-3191.
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abstract = "Background: Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. Methods and Results: Neointima formation was evaluated in PAl-1-deficient (PAI-1(-/-)) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001±0.001 mm2 in PAI-1(+/+) and 0.016±0.008 mm2 in PAI-1(-/-) mice within 1 week after electric injury (P<.02) and 0.055±0.008 mm2 in PAI-1(+/+) and 0.126±0.006 mm2 in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001). Proliferation of smooth muscle cells was not affected by PAl-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1(-/-) smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than Mid-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1(-/-) mice were intravenously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61±8 μg/mL with 2x109 plaque-forming units (pfu) virus. Luminal stenosis was 35±13{\%} in control AdRRS-treated (2x109 pfu) and suppressed to 5±5{\%} in AdCMVPAI-1-treated (6x108 pfu) PAI-1(-/-) mice (P<.002). Conclusions: By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.",
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T2 - A gene targeting and gene transfer study in mice

AU - Carmeliet, Peter

AU - Moons, Lieve

AU - Lijnen, Roger

AU - Janssens, Stefaan

AU - Lupu, Florea

AU - Collen, Désiré

AU - Gerard, Robert D.

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N2 - Background: Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. Methods and Results: Neointima formation was evaluated in PAl-1-deficient (PAI-1(-/-)) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001±0.001 mm2 in PAI-1(+/+) and 0.016±0.008 mm2 in PAI-1(-/-) mice within 1 week after electric injury (P<.02) and 0.055±0.008 mm2 in PAI-1(+/+) and 0.126±0.006 mm2 in PAI-1(-/-) mice within 3 weeks after mechanical injury (P<.001). Proliferation of smooth muscle cells was not affected by PAl-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1(-/-) smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than Mid-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1(-/-) mice were intravenously injected with replication-defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61±8 μg/mL with 2x109 plaque-forming units (pfu) virus. Luminal stenosis was 35±13% in control AdRRS-treated (2x109 pfu) and suppressed to 5±5% in AdCMVPAI-1-treated (6x108 pfu) PAI-1(-/-) mice (P<.002). Conclusions: By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.

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KW - Angioplasty

KW - Genetics

KW - Plasminogen

KW - Stenosis

KW - Viruses

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