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Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability.

Publication ,  Journal Article
Huang, N; Khan, A; Ashrafpour, H; Neligan, PC; Forrest, CR; Kontos, CD; Pang, CY
Published in: Am J Physiol Heart Circ Physiol
July 2006

Skin ischemic necrosis due to vasospasm and/or insufficient vascularity is the most common complication in the distal portion of the skin flap in reconstructive surgery. This project was designed to test our hypothesis that preoperative subdermal injection of adenoviral vectors encoding genes for vascular endothelial growth factor-165 (Ad.VEGF-165) or endothelial nitric oxide (NO) synthase (Ad.eNOS) effectively augments skin viability in skin flap surgery and that the mechanism of Ad.VEGF-165 gene therapy involves an increase in synthesis/release of the angiogenic and vasodilator factor NO. PBS (0.5 ml) or PBS containing Ad.VEGF-165, Ad.eNOS, or adenovirus (Ad.Null) was injected subdermally into the distal half of a mapped rat dorsal skin flap (4 x 10 cm) 7 days preoperatively, and skin flap viability was assessed 7 days postoperatively. Local subdermal gene therapy with 2 x 10(7)-2 x 10(10) plaque-forming units of VEGF-165 increased skin flap viability compared with PBS- or Ad.Null-injected control (P < 0.05). Subdermal Ad.VEGF-165 and Ad.eNOS gene therapies were equally effective in increasing skin flap viability at 5 x 10(8) plaque-forming units. Subdermal Ad.VEGF-165 therapy was associated with upregulation of eNOS protein expression, Ca2+ -dependent NOS activity, synthesis/release of NO, and increase in capillary density and blood flow in the distal portion of the skin flap. Injection of the NOS inhibitor Nomega-nitro-L-arginine (15 mg/kg im), but not the cyclooxygenase inhibitor indomethacin (5 mg/kg im), 45 min preoperatively completely abolished the increase in skin flap blood flow and viability induced by Ad.VEGF-165 injected subdermally into the mapped skin flap 7 days preoperatively. We have demonstrated for the first time that 1) Ad.VEGF-165 and Ad.eNOS mapped skin flap injected subdermally into the mapped skin flap 7 days preoperatively are equally effective in augmenting viability in the rat dorsal skin flap compared with control, 2) the mechanism of subdermal Ad.VEGF-165 gene therapy in augmenting skin flap viability involves an increase in NO synthesis/release downstream of upregulation of eNOS protein expression and Ca2+ -dependent NOS activity, and 3) the vasodilating effect of NO may predominantly mediate subdermal Ad.VEGF gene therapy in augmenting skin flap blood flow and viability.

Duke Scholars

Published In

Am J Physiol Heart Circ Physiol

DOI

ISSN

0363-6135

Publication Date

July 2006

Volume

291

Issue

1

Start / End Page

H127 / H137

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Treatment Outcome
  • Transfection
  • Tissue Survival
  • Tissue Culture Techniques
  • Surgical Flaps
  • Skin Transplantation
  • Skin
  • Rats, Sprague-Dawley
  • Rats
 

Citation

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Huang, N., Khan, A., Ashrafpour, H., Neligan, P. C., Forrest, C. R., Kontos, C. D., & Pang, C. Y. (2006). Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability. Am J Physiol Heart Circ Physiol, 291(1), H127–H137. https://doi.org/10.1152/ajpheart.01253.2005
Huang, Ning, Asim Khan, Homa Ashrafpour, Peter C. Neligan, Christopher R. Forrest, Christopher D. Kontos, and Cho Y. Pang. “Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability.Am J Physiol Heart Circ Physiol 291, no. 1 (July 2006): H127–37. https://doi.org/10.1152/ajpheart.01253.2005.
Huang N, Khan A, Ashrafpour H, Neligan PC, Forrest CR, Kontos CD, et al. Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability. Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H127–37.
Huang, Ning, et al. “Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability.Am J Physiol Heart Circ Physiol, vol. 291, no. 1, July 2006, pp. H127–37. Pubmed, doi:10.1152/ajpheart.01253.2005.
Huang N, Khan A, Ashrafpour H, Neligan PC, Forrest CR, Kontos CD, Pang CY. Efficacy and mechanism of adenovirus-mediated VEGF-165 gene therapy for augmentation of skin flap viability. Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H127–H137.

Published In

Am J Physiol Heart Circ Physiol

DOI

ISSN

0363-6135

Publication Date

July 2006

Volume

291

Issue

1

Start / End Page

H127 / H137

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Treatment Outcome
  • Transfection
  • Tissue Survival
  • Tissue Culture Techniques
  • Surgical Flaps
  • Skin Transplantation
  • Skin
  • Rats, Sprague-Dawley
  • Rats