Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation

Amir Dorafshar, Niren Angle, Michael Bryer-Ash, Danshan Huang, Michael M. Farooq, Hugh A. Gelabert, Julie A. Freischlag

Research output: Contribution to journalArticle

Abstract

Introduction. Delivery of vascular endothelial growth factor (VEGF) protein or gene transfer has been shown to accelerate re-endothelialization and attenuate neointimal hyperplasia in various arterial injury models, including balloon injury, stent implantation, and vein grafts. In addition to stimulating re-endothelialization, we hypothesize that VEGF has further vascular protective functions to prevent neointimal hyperplasia by directly inhibiting mitogen-induced proliferation of vascular smooth muscle cells (VSMCs) via the mitogen-activated protein kinase pathway. Materials and methods. Human aortic VSMCs were seeded and serum starved for 24 h. The cells were then stimulated with a mitogen, recombinant human platelet derived growth factor at 20 ng/mL together with 0, 10, 20, 30, 40, 50 ng/mL recombinant human VEGF. A proliferation assay was used to quantitate bromodeoxyuridine uptake into newly synthesized DNA. Western immunoassay was used to quantify extracellular signal-regulated kinase (ERK) 2 protein and phosphorylation of retinoblastoma and ERK 1/2 protein. Results. VEGF inhibited bromodeoxyuridine incorporation into mitogen-induced VSMC in a dose-dependent manner, reaching statistical significance at concentrations of 30 (P <0.05), 40 (P <0.05), and 50 ng/mL (P <0.01). Densitometry of western immunoblots revealed an inhibition of phosphorylation of retinoblastoma at VEGF concentrations of 40 and 50 ng/mL and ERK 1/2 phosphorylation at concentrations of 30, 40 and 50 ng/mL. Conclusion. In addition to stimulating re-endothelialization, VEGF appears to have a vascular protective function by directly inhibiting VSMC proliferation. This effect occurs in the absence of endothelial cells and via the mitogen-activated protein kinase pathway. VEGF may serve as an important modulator of mitogen-induced VSMC proliferation after vascular injury.

Original languageEnglish (US)
Pages (from-to)179-186
Number of pages8
JournalJournal of Surgical Research
Volume114
Issue number2
DOIs
StatePublished - Oct 2003
Externally publishedYes

Fingerprint

Vascular Smooth Muscle
Mitogens
Vascular Endothelial Growth Factor A
Smooth Muscle Myocytes
Cell Proliferation
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Phosphorylation
Bromodeoxyuridine
Mitogen-Activated Protein Kinases
Hyperplasia
Blood Vessels
Retinoblastoma Protein
Retinoblastoma
Densitometry
Vascular System Injuries
Platelet-Derived Growth Factor
Wounds and Injuries
Immunoassay
Stents

Keywords

  • Human aortic smooth muscle
  • Neointimal hyperplasia
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Surgery

Cite this

Dorafshar, A., Angle, N., Bryer-Ash, M., Huang, D., Farooq, M. M., Gelabert, H. A., & Freischlag, J. A. (2003). Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation. Journal of Surgical Research, 114(2), 179-186. https://doi.org/10.1016/S0022-4804(03)00254-3

Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation. / Dorafshar, Amir; Angle, Niren; Bryer-Ash, Michael; Huang, Danshan; Farooq, Michael M.; Gelabert, Hugh A.; Freischlag, Julie A.

In: Journal of Surgical Research, Vol. 114, No. 2, 10.2003, p. 179-186.

Research output: Contribution to journalArticle

Dorafshar, A, Angle, N, Bryer-Ash, M, Huang, D, Farooq, MM, Gelabert, HA & Freischlag, JA 2003, 'Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation', Journal of Surgical Research, vol. 114, no. 2, pp. 179-186. https://doi.org/10.1016/S0022-4804(03)00254-3
Dorafshar, Amir ; Angle, Niren ; Bryer-Ash, Michael ; Huang, Danshan ; Farooq, Michael M. ; Gelabert, Hugh A. ; Freischlag, Julie A. / Vascular endothelial growth factor inhibits mitogen-induced vascular smooth muscle cell proliferation. In: Journal of Surgical Research. 2003 ; Vol. 114, No. 2. pp. 179-186.
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abstract = "Introduction. Delivery of vascular endothelial growth factor (VEGF) protein or gene transfer has been shown to accelerate re-endothelialization and attenuate neointimal hyperplasia in various arterial injury models, including balloon injury, stent implantation, and vein grafts. In addition to stimulating re-endothelialization, we hypothesize that VEGF has further vascular protective functions to prevent neointimal hyperplasia by directly inhibiting mitogen-induced proliferation of vascular smooth muscle cells (VSMCs) via the mitogen-activated protein kinase pathway. Materials and methods. Human aortic VSMCs were seeded and serum starved for 24 h. The cells were then stimulated with a mitogen, recombinant human platelet derived growth factor at 20 ng/mL together with 0, 10, 20, 30, 40, 50 ng/mL recombinant human VEGF. A proliferation assay was used to quantitate bromodeoxyuridine uptake into newly synthesized DNA. Western immunoassay was used to quantify extracellular signal-regulated kinase (ERK) 2 protein and phosphorylation of retinoblastoma and ERK 1/2 protein. Results. VEGF inhibited bromodeoxyuridine incorporation into mitogen-induced VSMC in a dose-dependent manner, reaching statistical significance at concentrations of 30 (P <0.05), 40 (P <0.05), and 50 ng/mL (P <0.01). Densitometry of western immunoblots revealed an inhibition of phosphorylation of retinoblastoma at VEGF concentrations of 40 and 50 ng/mL and ERK 1/2 phosphorylation at concentrations of 30, 40 and 50 ng/mL. Conclusion. In addition to stimulating re-endothelialization, VEGF appears to have a vascular protective function by directly inhibiting VSMC proliferation. This effect occurs in the absence of endothelial cells and via the mitogen-activated protein kinase pathway. VEGF may serve as an important modulator of mitogen-induced VSMC proliferation after vascular injury.",
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AU - Dorafshar, Amir

AU - Angle, Niren

AU - Bryer-Ash, Michael

AU - Huang, Danshan

AU - Farooq, Michael M.

AU - Gelabert, Hugh A.

AU - Freischlag, Julie A.

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N2 - Introduction. Delivery of vascular endothelial growth factor (VEGF) protein or gene transfer has been shown to accelerate re-endothelialization and attenuate neointimal hyperplasia in various arterial injury models, including balloon injury, stent implantation, and vein grafts. In addition to stimulating re-endothelialization, we hypothesize that VEGF has further vascular protective functions to prevent neointimal hyperplasia by directly inhibiting mitogen-induced proliferation of vascular smooth muscle cells (VSMCs) via the mitogen-activated protein kinase pathway. Materials and methods. Human aortic VSMCs were seeded and serum starved for 24 h. The cells were then stimulated with a mitogen, recombinant human platelet derived growth factor at 20 ng/mL together with 0, 10, 20, 30, 40, 50 ng/mL recombinant human VEGF. A proliferation assay was used to quantitate bromodeoxyuridine uptake into newly synthesized DNA. Western immunoassay was used to quantify extracellular signal-regulated kinase (ERK) 2 protein and phosphorylation of retinoblastoma and ERK 1/2 protein. Results. VEGF inhibited bromodeoxyuridine incorporation into mitogen-induced VSMC in a dose-dependent manner, reaching statistical significance at concentrations of 30 (P <0.05), 40 (P <0.05), and 50 ng/mL (P <0.01). Densitometry of western immunoblots revealed an inhibition of phosphorylation of retinoblastoma at VEGF concentrations of 40 and 50 ng/mL and ERK 1/2 phosphorylation at concentrations of 30, 40 and 50 ng/mL. Conclusion. In addition to stimulating re-endothelialization, VEGF appears to have a vascular protective function by directly inhibiting VSMC proliferation. This effect occurs in the absence of endothelial cells and via the mitogen-activated protein kinase pathway. VEGF may serve as an important modulator of mitogen-induced VSMC proliferation after vascular injury.

AB - Introduction. Delivery of vascular endothelial growth factor (VEGF) protein or gene transfer has been shown to accelerate re-endothelialization and attenuate neointimal hyperplasia in various arterial injury models, including balloon injury, stent implantation, and vein grafts. In addition to stimulating re-endothelialization, we hypothesize that VEGF has further vascular protective functions to prevent neointimal hyperplasia by directly inhibiting mitogen-induced proliferation of vascular smooth muscle cells (VSMCs) via the mitogen-activated protein kinase pathway. Materials and methods. Human aortic VSMCs were seeded and serum starved for 24 h. The cells were then stimulated with a mitogen, recombinant human platelet derived growth factor at 20 ng/mL together with 0, 10, 20, 30, 40, 50 ng/mL recombinant human VEGF. A proliferation assay was used to quantitate bromodeoxyuridine uptake into newly synthesized DNA. Western immunoassay was used to quantify extracellular signal-regulated kinase (ERK) 2 protein and phosphorylation of retinoblastoma and ERK 1/2 protein. Results. VEGF inhibited bromodeoxyuridine incorporation into mitogen-induced VSMC in a dose-dependent manner, reaching statistical significance at concentrations of 30 (P <0.05), 40 (P <0.05), and 50 ng/mL (P <0.01). Densitometry of western immunoblots revealed an inhibition of phosphorylation of retinoblastoma at VEGF concentrations of 40 and 50 ng/mL and ERK 1/2 phosphorylation at concentrations of 30, 40 and 50 ng/mL. Conclusion. In addition to stimulating re-endothelialization, VEGF appears to have a vascular protective function by directly inhibiting VSMC proliferation. This effect occurs in the absence of endothelial cells and via the mitogen-activated protein kinase pathway. VEGF may serve as an important modulator of mitogen-induced VSMC proliferation after vascular injury.

KW - Human aortic smooth muscle

KW - Neointimal hyperplasia

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