Deep vein thrombosis resolution is not accelerated with increased neovascularization

Manu R. Varma, Daria Moaveni, Nicholas A. Dewyer, Andrea J. Varga, K. Barry Deatrick, Steven L. Kunkel, Gilbert R. Upchurch, Thomas W. Wakefield, Peter K. Henke

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Introduction Deep venous thrombosis (DVT) resolution involves fibrinolysis, neovascularization, and fibrosis. We hypothesized that promoting neovascularization would accelerate DVT resolution. Methods A rat model of stasis DVT was produced with proximal ligation of the inferior vena cava (IVC) and all visible tributaries. One μg of interferon inducible protein (IP-10; angiostatic chemokine), basic fibroblast growth factor (bFGF; pro-angiogenic cytokine), epithelial neutrophil activating protein (ENA-78; pro-angiogenic chemokine), or saline solution control was injected into the IVC after ligation, and then via tail vein injection daily until sacrifice at either 4 or 8 days. Peripheral blood counts were measured, and thrombus weight was recorded at sacrifice. Laser Doppler in vivo imaging was used to estimate post-thrombotic IVC blood flow. Immunohistologic assessment of the thrombosed IVC for polymorphonuclear neutrophils (PMNs), monocytes (ED-1), and laminin (neovascular channels) was performed or the thrombus was separated from the IVC and assayed for keratinocyte cytokine (KC), monocyte chemotactic protein-1 (MCP-1), bFGF with enzyme-linked immunosorbent assay (ELISA), and total collagen with a direct colorimetric assay. Results Peripheral blood and intrathrombus PMNs and monocytes were not significantly different in the treated or control rats. There were no differences in any measure at 4 days. At 8 days, thrombus neovascularity, but not weight or collagen content, was increased in rats treated with bFGF or ENA-78 compared with control rats (17.6 ± 0.93, 16.2 ± 0.97 vs 13.2 ± 0.79; channels/5 high-power fields (hpf; n = 6-10; P < .05). Post DVT IVC blood flow was significantly increased in bFGF-treated rats but not in rats treated with IP-10 or ENA-78, as compared with control rats. Rats treated with ENA-78 had increased intrathrombus bFGF compared with control rats (85 ± 27 pg/mg protein vs 20 ± 6 pg/mg protein; n = 6; P < .05), but other mediators were not significantly different in treated rats compared with control rats. Conclusion Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution.

Original languageEnglish (US)
Pages (from-to)536-542
Number of pages7
JournalJournal of Vascular Surgery
Volume40
Issue number3
DOIs
StatePublished - Sep 2004
Externally publishedYes

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Venous Thrombosis
Inferior Vena Cava
Thrombosis
Neutrophils
Chemokines
Ligation
Monocytes
Collagen
Chemokine CXCL10
Cytokines
Weights and Measures
Proteins
Chemokine CCL2
Fibrinolysis
Fibroblast Growth Factor 2
Keratinocytes
Sodium Chloride
Tail
Veins
Lasers

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Varma, M. R., Moaveni, D., Dewyer, N. A., Varga, A. J., Deatrick, K. B., Kunkel, S. L., ... Henke, P. K. (2004). Deep vein thrombosis resolution is not accelerated with increased neovascularization. Journal of Vascular Surgery, 40(3), 536-542. https://doi.org/10.1016/j.jvs.2004.05.023

Deep vein thrombosis resolution is not accelerated with increased neovascularization. / Varma, Manu R.; Moaveni, Daria; Dewyer, Nicholas A.; Varga, Andrea J.; Deatrick, K. Barry; Kunkel, Steven L.; Upchurch, Gilbert R.; Wakefield, Thomas W.; Henke, Peter K.

In: Journal of Vascular Surgery, Vol. 40, No. 3, 09.2004, p. 536-542.

Research output: Contribution to journalArticle

Varma, MR, Moaveni, D, Dewyer, NA, Varga, AJ, Deatrick, KB, Kunkel, SL, Upchurch, GR, Wakefield, TW & Henke, PK 2004, 'Deep vein thrombosis resolution is not accelerated with increased neovascularization', Journal of Vascular Surgery, vol. 40, no. 3, pp. 536-542. https://doi.org/10.1016/j.jvs.2004.05.023
Varma, Manu R. ; Moaveni, Daria ; Dewyer, Nicholas A. ; Varga, Andrea J. ; Deatrick, K. Barry ; Kunkel, Steven L. ; Upchurch, Gilbert R. ; Wakefield, Thomas W. ; Henke, Peter K. / Deep vein thrombosis resolution is not accelerated with increased neovascularization. In: Journal of Vascular Surgery. 2004 ; Vol. 40, No. 3. pp. 536-542.
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abstract = "Introduction Deep venous thrombosis (DVT) resolution involves fibrinolysis, neovascularization, and fibrosis. We hypothesized that promoting neovascularization would accelerate DVT resolution. Methods A rat model of stasis DVT was produced with proximal ligation of the inferior vena cava (IVC) and all visible tributaries. One μg of interferon inducible protein (IP-10; angiostatic chemokine), basic fibroblast growth factor (bFGF; pro-angiogenic cytokine), epithelial neutrophil activating protein (ENA-78; pro-angiogenic chemokine), or saline solution control was injected into the IVC after ligation, and then via tail vein injection daily until sacrifice at either 4 or 8 days. Peripheral blood counts were measured, and thrombus weight was recorded at sacrifice. Laser Doppler in vivo imaging was used to estimate post-thrombotic IVC blood flow. Immunohistologic assessment of the thrombosed IVC for polymorphonuclear neutrophils (PMNs), monocytes (ED-1), and laminin (neovascular channels) was performed or the thrombus was separated from the IVC and assayed for keratinocyte cytokine (KC), monocyte chemotactic protein-1 (MCP-1), bFGF with enzyme-linked immunosorbent assay (ELISA), and total collagen with a direct colorimetric assay. Results Peripheral blood and intrathrombus PMNs and monocytes were not significantly different in the treated or control rats. There were no differences in any measure at 4 days. At 8 days, thrombus neovascularity, but not weight or collagen content, was increased in rats treated with bFGF or ENA-78 compared with control rats (17.6 ± 0.93, 16.2 ± 0.97 vs 13.2 ± 0.79; channels/5 high-power fields (hpf; n = 6-10; P < .05). Post DVT IVC blood flow was significantly increased in bFGF-treated rats but not in rats treated with IP-10 or ENA-78, as compared with control rats. Rats treated with ENA-78 had increased intrathrombus bFGF compared with control rats (85 ± 27 pg/mg protein vs 20 ± 6 pg/mg protein; n = 6; P < .05), but other mediators were not significantly different in treated rats compared with control rats. Conclusion Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution.",
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AU - Moaveni, Daria

AU - Dewyer, Nicholas A.

AU - Varga, Andrea J.

AU - Deatrick, K. Barry

AU - Kunkel, Steven L.

AU - Upchurch, Gilbert R.

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N2 - Introduction Deep venous thrombosis (DVT) resolution involves fibrinolysis, neovascularization, and fibrosis. We hypothesized that promoting neovascularization would accelerate DVT resolution. Methods A rat model of stasis DVT was produced with proximal ligation of the inferior vena cava (IVC) and all visible tributaries. One μg of interferon inducible protein (IP-10; angiostatic chemokine), basic fibroblast growth factor (bFGF; pro-angiogenic cytokine), epithelial neutrophil activating protein (ENA-78; pro-angiogenic chemokine), or saline solution control was injected into the IVC after ligation, and then via tail vein injection daily until sacrifice at either 4 or 8 days. Peripheral blood counts were measured, and thrombus weight was recorded at sacrifice. Laser Doppler in vivo imaging was used to estimate post-thrombotic IVC blood flow. Immunohistologic assessment of the thrombosed IVC for polymorphonuclear neutrophils (PMNs), monocytes (ED-1), and laminin (neovascular channels) was performed or the thrombus was separated from the IVC and assayed for keratinocyte cytokine (KC), monocyte chemotactic protein-1 (MCP-1), bFGF with enzyme-linked immunosorbent assay (ELISA), and total collagen with a direct colorimetric assay. Results Peripheral blood and intrathrombus PMNs and monocytes were not significantly different in the treated or control rats. There were no differences in any measure at 4 days. At 8 days, thrombus neovascularity, but not weight or collagen content, was increased in rats treated with bFGF or ENA-78 compared with control rats (17.6 ± 0.93, 16.2 ± 0.97 vs 13.2 ± 0.79; channels/5 high-power fields (hpf; n = 6-10; P < .05). Post DVT IVC blood flow was significantly increased in bFGF-treated rats but not in rats treated with IP-10 or ENA-78, as compared with control rats. Rats treated with ENA-78 had increased intrathrombus bFGF compared with control rats (85 ± 27 pg/mg protein vs 20 ± 6 pg/mg protein; n = 6; P < .05), but other mediators were not significantly different in treated rats compared with control rats. Conclusion Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution.

AB - Introduction Deep venous thrombosis (DVT) resolution involves fibrinolysis, neovascularization, and fibrosis. We hypothesized that promoting neovascularization would accelerate DVT resolution. Methods A rat model of stasis DVT was produced with proximal ligation of the inferior vena cava (IVC) and all visible tributaries. One μg of interferon inducible protein (IP-10; angiostatic chemokine), basic fibroblast growth factor (bFGF; pro-angiogenic cytokine), epithelial neutrophil activating protein (ENA-78; pro-angiogenic chemokine), or saline solution control was injected into the IVC after ligation, and then via tail vein injection daily until sacrifice at either 4 or 8 days. Peripheral blood counts were measured, and thrombus weight was recorded at sacrifice. Laser Doppler in vivo imaging was used to estimate post-thrombotic IVC blood flow. Immunohistologic assessment of the thrombosed IVC for polymorphonuclear neutrophils (PMNs), monocytes (ED-1), and laminin (neovascular channels) was performed or the thrombus was separated from the IVC and assayed for keratinocyte cytokine (KC), monocyte chemotactic protein-1 (MCP-1), bFGF with enzyme-linked immunosorbent assay (ELISA), and total collagen with a direct colorimetric assay. Results Peripheral blood and intrathrombus PMNs and monocytes were not significantly different in the treated or control rats. There were no differences in any measure at 4 days. At 8 days, thrombus neovascularity, but not weight or collagen content, was increased in rats treated with bFGF or ENA-78 compared with control rats (17.6 ± 0.93, 16.2 ± 0.97 vs 13.2 ± 0.79; channels/5 high-power fields (hpf; n = 6-10; P < .05). Post DVT IVC blood flow was significantly increased in bFGF-treated rats but not in rats treated with IP-10 or ENA-78, as compared with control rats. Rats treated with ENA-78 had increased intrathrombus bFGF compared with control rats (85 ± 27 pg/mg protein vs 20 ± 6 pg/mg protein; n = 6; P < .05), but other mediators were not significantly different in treated rats compared with control rats. Conclusion Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution.

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