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J Reconstr Microsurg 2005; 21(6): 391-396
DOI: 10.1055/s-2005-915207
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Vascular Endothelial Growth Factor Gene Therapy in Improvement of Skin Paddle Survival in a Rat TRAM Flap Model

Feng Zhang1 , Feixue Yang1 , Eric C. Hu1 , William Sones1 , Manping Lei1 , William C. Lineaweaver1
  • 1Division of Plastic Surgery, University of Mississippi Medical Center, Jackson, Mississippi
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Publication History

Accepted: Apirl 13, 2005

Publication Date:
12 August 2005 (online)

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ABSTRACT

The use of growth factors in inducing angiogenesis and enhancing flap viability has provided promising results. Targeted gene therapy has evolved in hopes of increasing the longevity and effectiveness of these growth factor treatments. The purpose of this study was to examine the effect of preoperative treatment by vascular endothelial growth factor (VEGF) plasmid DNA on the survival of the skin paddle in a rat pedicled TRAM flap model. In part one of the study, VEGF plasmid DNA incorporated with lipofectamine was injected into the subcutaneous fascial layer of the upper abdominal walls of the rats. At 4 days postoperatively, biopsies were taken from the injected area for histology and VEGF protein quantification. In part two of the study, the rats were divided into three groups. In one experimental group, the VEGF plasmid DNA was injected into the subcutaneous fascial layer in the area where the TRAM flap would be elevated. In two control groups, the plasmid without VEGF DNA and saline were injected. The flaps were raised and replaced 4 days after injection. Flap survival was examined. Results showed that tissue receiving VEGF plasmid DNA injection revealed new vessel sprouting. The VEGF levels in these tissues were significantly higher than in the tissue not receiving VEGF plasmid DNA. In flap survival, the mean viable area of the skin paddles receiving preoperative VEGF plasmid DNA injection was significantly larger than that of flaps receiving no VEGF plasmid DNA and saline injection. This study demonstrated that preoperative subcutaneous injection of VEGF plasmid DNA could induce angiogenesis and improve TRAM skin paddle survival.

KEYWORDS

VEGF gene therapy - TRAM flap skin paddle survival

REFERENCES

  • 1 Knight K R. Review of postoperative pharmacological infusions in ischemic skin flaps.  Microsurgery. 1994;  15 675-684
    CrossrefPubMedSearch in Google Scholar
  • 2 Pang C Y, Forrest C R, Morris S F. Pharmacological augmentation of skin flap viability: a hypothesis to mimic the surgical delay phenomenon or a wishful thought.  Ann Plast Surg. 1989;  22 293-306
    CrossrefPubMedSearch in Google Scholar
  • 3 Pang C Y, Forrest C R. Acute pharmacologic preconditioning as a new concept and alternative approach for prevention of skeletal muscle ischemic necrosis.  Biochem Pharmacol. 1995;  49 1023-1034
    CrossrefPubMedSearch in Google Scholar
  • 4 Steed D L. The role of growth factors in wound healing.  Surg Clin North Am. 1997;  77 575-586
    CrossrefPubMedSearch in Google Scholar
  • 5 Robinson C J. Growth factors: therapeutic advances in wound healing.  Ann Med. 1993;  25 535-538
    PubMedSearch in Google Scholar
  • 6 Lu W W, Ip W Y, Jing W M, Holmes A D, Chow S P. Biomechanical properties of thin skin flap after basic fibroblast growth factor (bFGF) administration.  Br J Plast Surg. 2000;  53 225-229
    CrossrefPubMedSearch in Google Scholar
  • 7 Nall A V, Brownlee R E, Colvin C P et al.. Transforming growth factor beta 1 improves wound healing and random flap survival in normal and irradiated rats.  Arch Otolaryngol Head Neck Surg. 1996;  122 171-177
    PubMedSearch in Google Scholar
  • 8 Hom D B, Assefa G. Effects of endothelial cell growth factor on vascular compromised skin flaps.  Arch Otolaryngol Head Neck Surg. 1992;  118 624-628
    PubMedSearch in Google Scholar
  • 9 Ishiguro N, Yabe Y, Shimizu T, Iwata H, Miura T. Basic fibroblast growth factor has a beneficial effect on the viability of random skin flaps in rats.  Ann Plast Surg. 1994;  32 356-360
    CrossrefPubMedSearch in Google Scholar
  • 10 Rashid M A, Akita S, Razzaque M S et al.. Coadministration of basic fibroblast growth factor and sucrose octasulfate (sucralfate) facilitates the rat dorsal flap survival and viability.  Plast Reconstr Surg. 1999;  103 941-948
    PubMedSearch in Google Scholar
  • 11 Rumalla V K, Borah G L. Cytokines, growth factors, and plastic surgery.  Plast Reconstr Surg. 2001;  108 719-733
    PubMedSearch in Google Scholar
  • 12 Tepper O M, Mehrara B J. Gene therapy in plastic surgery. Plast Reconstr Surg.  2002;  109 716-734
    PubMedSearch in Google Scholar
  • 13 Taub P J, Marmur J D, Zhang W X et al.. Locally administered vascular endothelial growth factor cDNA increases survival of ischemic experimental skin flaps.  Plast Reconstr Surg. 1998;  102 2033-2209
    PubMedSearch in Google Scholar
  • 14 Taub P J, Marmur J D, Zhang W X et al.. Effect of time on the viability of ischemic skin flaps treated with vascular endothelial growth factor (VEGF) cDNA.  J Reconstr Microsurg. 1998;  14 387-390
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 O'Toole G, MacKenzie D, Lindeman R et al.. Vascular endothelial growth factor gene therapy in ischaemic rat skin flaps.  Br J Plast Surg. 2002;  55 55-58
    CrossrefPubMedSearch in Google Scholar
  • 16 Lubiatowski P, Gurunluoglu R, Goldman C K, Skugor B, Carnevale K, Siemionow M. Gene therapy by adenovirus-mediated vascular endothelial growth factor and angiopoietin-1 promotes perfusion of muscle flaps.  Plast Reconstr Surg. 2002;  110 149-159
    PubMedSearch in Google Scholar
  • 17 Gurunluoglu R, Ozer K, Skugor B, Lubiatowski P, Carnevale K, Siemionow M. Effect of transfection time on the survival of epigastric skin flaps pretreated with adenovirus encoding the VEGF gene.  Ann Plast Surg. 2002;  49 161-169
    CrossrefPubMedSearch in Google Scholar
  • 18 Shrotria S, Webster D J, Mansel R E, Hughes L E. Complications of rectus abdominis myocutaneous flaps in breast surgery.  Eur J Surg Oncol. 1993;  19 80-83
    PubMedSearch in Google Scholar
  • 19 Carlson G W. Breast reconstruction: surgical options and patient selection.  Cancer. 1994;  74 436-439
    PubMedSearch in Google Scholar
  • 20 Paige K T, Bostwick J, Bried J T, Jones G. A comparison of morbidity from bilateral, unipedicled and unilateral, unipedicled TRAM flap breast reconstructions.  Plast Reconstr Surg. 1998;  101 1819-1827
    CrossrefPubMedSearch in Google Scholar
  • 21 Kroll S S, Reece G P, Miller M J, Schusterman M A. Comparison of the rectus abdominis free flap with the pectoralis major myocutaneous flap for reconstructions of the head and neck.  Am J Surg. 1992;  164 615-618
    PubMedSearch in Google Scholar
  • 22 Ribuffo D, Muratori L, Antoniadou K et al.. A hemodynamic approach to clinical results in the TRAM flap after selective delay.  Plast Reconstr Surg. 1997;  99 1706-1714
    PubMedSearch in Google Scholar
  • 23 Hudson D A. The surgically delayed unipedicled TRAM flap for breast reconstruction.  Ann Plast Surg. 1996;  36 238-245
    PubMedSearch in Google Scholar
  • 24 Erdmann D, Sundin B M, Moquin K J, Young H, Georgiade G S. Delay in unipedicled TRAM flap reconstruction of the breast: a review of 76 consecutive cases.  Plast Reconstr Surg. 2002;  110 762-767
    CrossrefPubMedSearch in Google Scholar
  • 25 Hebda P A, Klingbeil C K, Abraham J A, Fiddes J C. Basic fibroblast growth factor stimulation of epidermal wound healing in pigs.  J Invest Dermatol. 1990;  95 626-631
    CrossrefPubMedSearch in Google Scholar
  • 26 Pu L Q, Sniderman A D, Arekat Z, Graham A M, Brassard R, Symes J F. Angiogenic growth factor and revascularization of the ischemic limb: evaluation in a rabbit model.  J Surg Res. 1993;  54 575-583
    CrossrefPubMedSearch in Google Scholar
  • 27 Takeshita S, Rossow S T, Kearney M et al.. Time course of increased cellular proliferation in collateral arteries after administration of vascular endothelial growth factor in a rabbit model of lower limb vascular insufficiency.  Am J Pathol. 1995;  147 1649-1660
    PubMedSearch in Google Scholar
  • 28 Zhang F, Fischer K, Komorowska-Timek E et al.. Improvement of skin paddle survival by application of vascular endothelial growth factor in a rat TRAM flap model.  Ann Plast Surg. 2001;  46 314-319
    CrossrefPubMedSearch in Google Scholar
  • 29 Seify H, Bulky U, Jones G. Effect of vascular endothelial growth factor-induced angiogenesis on TRAM flap harvesting after abdominoplasty.  Plast Reconstr Surg. 2003;  111 1212-1216
    CrossrefPubMedSearch in Google Scholar
  • 30 Pu L L, Ahmed S, Thomson J G, Reid M A, Madsen J A, Restifo R J. Endothelial cell growth factor enhances musculocutaneous flap survival through the process of neovascularization.  Ann Plast Surg. 1999;  42 306-312
    PubMedSearch in Google Scholar
  • 31 Kryger Z, Zhang F, Dogan T, Cheng C, Lineaweaver W C, Buncke H J. The effects of VEGF on survival of a random flap in the rat: examination of various routes of administration.  Br J Plast Surg. 2000;  53 234-239
    CrossrefPubMedSearch in Google Scholar
  • 32 Shima D T, Deutsch U, D'Amore P A. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability.  FEBS Lett. 1995;  370 203-208
    CrossrefPubMedSearch in Google Scholar
  • 33 Plautz G E, Nabel E G, Fox B et al.. Direct gene transfer for the understanding and treatment of human disease.  Ann NY Acad Sci. 1994;  716 144-153
    PubMedSearch in Google Scholar
  • 34 Ghazizadeh S, Taichman L B. Virus-mediated gene transfer for cutaneous gene therapy.  Hum Gene Ther. 2000;  11 2247-2251
    CrossrefPubMedSearch in Google Scholar
  • 35 Rasmussen H S, Rasmussen C S, Macko J. VEGF gene therapy for coronary artery disease and peripheral vascular disease.  Cardiovasc Radiat Med. 2002;  3 114-117
    CrossrefPubMedSearch in Google Scholar
  • 36 Baumgartner I, Rauh G, Pieczek A et al.. Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor.  Ann Intern Med. 2000;  132 880-884
    PubMedSearch in Google Scholar
  • 37 Flamme I, von Reutern M, Drexler H C, Syed-Ali S, Risau W. Overexpression of vascular endothelial growth factor in the avian embryo induces hypervascularization and increased vascular permeability without alterations of embryonic pattern formation.  Dev Biol. 1995;  171 399-414
    CrossrefPubMedSearch in Google Scholar
  • 38 Hippenstiel S, Krull M, Ikemann A, Risau W, Clauss M, Suttorp N. VEGF induces hyperpermeability by a direct action on endothelial cells.  Am J Physiol. 1998;  274 L678-L684
    PubMedSearch in Google Scholar
  • 39 Nicosia R F, Lin Y J, Hazelton D, Qian X H. Endogenous regulation of angiogenesis in the rat aorta model: role of vascular endothelial growth factor.  Am J Pathol. 1997;  151 1379-1386
    PubMedSearch in Google Scholar
  • 40 Phillips G D, Stone A M, Jones B D, Schultz J C, Whitehead R A, Knighton D R. Vascular endothelial growth factor (rhVEGF165) stimulates direct angiogenesis in the rabbit cornea.  In Vivo. 1994;  8 961-965
    PubMedSearch in Google Scholar
  • 41 Magovern C J, Mack C A, Zhang J, Rosengart T K, Isom O W, Crystal R G. Regional angiogenesis induced in nonischemic tissue by an adnoviral vector expressing vascular endothelial growth factor.  Hum Gene Ther. 1997;  8 215-227
    PubMedSearch in Google Scholar
  • 42 Nabel E G, Gordon D, Yang Z Y et al.. Gene transfer in vivo with DNA-liposome complexes: lack of autoimmunity and gonadal localization.  Hum Gene Ther. 1992;  3 649-656
    PubMedSearch in Google Scholar

Feng ZhangM.D. Ph.D. 

Division of Plastic Surgery, University of Mississippi Medical Center

2500 North State Street, Jackson, MS 39216