Effects of Vascular Endothelial Growth Factor on Survival of Surgical Flaps: A Review of Experimental Studies

Taolin Fang; William C. Lineaweaver; Michael B. Chen; Carson Kisner; Feng Zhang

doi:10.1055/s-0033-1345429

Journal of Reconstructive Microsurgery, Inhaltsverzeichnis

J Reconstr Microsurg 2014; 30(01): 001-014
DOI: 10.1055/s-0033-1345429

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of Vascular Endothelial Growth Factor on Survival of Surgical Flaps: A Review of Experimental Studies

Taolin Fang

¹Division of Plastic Surgery, University of Mississippi Medical Center, Jackson, Mississippi

²Department of Orthopaedics, Zhongshan Hospital Fudan University, Shanghai, China

,

William C. Lineaweaver

³JMS Burn and Reconstructive Center, Crossgates River Oaks Hospital, Brandon, Mississippi

,

Michael B. Chen

¹Division of Plastic Surgery, University of Mississippi Medical Center, Jackson, Mississippi

,

Carson Kisner

¹Division of Plastic Surgery, University of Mississippi Medical Center, Jackson, Mississippi

,

Feng Zhang

¹Division of Plastic Surgery, University of Mississippi Medical Center, Jackson, Mississippi

› Institutsangaben

Abstract

Partial or complete necrosis of skin flaps remains a significant problem in plastic and reconstructive surgery. Growth factors have shown promise in improving flap survival through increased angiogenesis and blood supply to the flap. Vascular endothelial growth factor (VEGF) is the most widely investigated and successful one. But the mechanisms of the effects are still not very clear. In the course of a series of experiments, we indicated that tissue survival of surgical flaps could be improved by both preoperative (sustained phase effect) and intraoperative (acute phase effect) application of VEGF. We reviewed both experimental and clinical investigations on the use of VEGF with surgical flaps to summarize the evidence of both phases of VEGF activity in promotion of flaps survival in detail. With the combinations of acute and sustained phases of effects, VEGF protein and gene, VEGF morphologic actions, and VEGF histochemical modulations suggest a pattern of VEGF activity that can be superimposed on classic descriptive mechanisms of tissue survival of flaps.

Keywords

flaps - vascular endothelial growth factor - mechanism

Volltext

Referenzen

References
1 Sværdborg M, Birke-Sørensen H. Monitored extended secondary arterial ischemia in a free muscle transfer. J Reconstr Microsurg 2012; 28 (2) 119-124
2 Kwee MM, Rozen WM, Ting JWC, Mirkazemi M, Leong J, Baillieu C. Total scalp reconstruction with bilateral anterolateral thigh flaps. Microsurgery 2012; 32 (5) 393-396
3 Kerrigan CL, Stotland MA. Ischemia reperfusion injury: a review. Microsurgery 1993; 14 (3) 165-175
4 Carroll WR, Esclamado RM. Ischemia/reperfusion injury in microvascular surgery. Head Neck 2000; 22 (7) 700-713
5 Pang CY. Ischemia-induced reperfusion injury in muscle flaps: pathogenesis and major source of free radicals. J Reconstr Microsurg 1990; 6 (1) 77-83
6 Balasubramanian D, Thankappan K, Kuriakose MA , et al. Reconstructive indications of simultaneous double free flaps in the head and neck: a case series and literature review. Microsurgery 2012; 32 (6) 423-430
7 Haughey BH, Panje WR. Extension of the musculocutaneous flap by surgical delay. Arch Otolaryngol 1985; 111 (4) 234-240
8 Taylor GI, Corlett RJ, Caddy CM, Zelt RG. An anatomic review of the delay phenomenon: II. Clinical applications. Plast Reconstr Surg 1992; 89 (3) 408-416 , discussion 417–418
9 Attinger CE, Picken CA, Troost TR, Sessions RB. Minimizing pectoralis myocutaneous flap loss with the delay principle. Otolaryngol Head Neck Surg 1996; 114 (1) 148-157
10 Grabb W , ed. Basic techniques of plastic surgery. Boston: Little Brown; 1986
11 Huang N, Khan A, Ashrafpour H , 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; 291 (1) H127-H137
12 Knight KR. Review of postoperative pharmacological infusions in ischemic skin flaps. Microsurgery 1994; 15 (10) 675-684
13 Pang CY, Forrest CR, Morris SF. Pharmacological augmentation of skin flap viability: a hypothesis to mimic the surgical delay phenomenon or a wishful thought. Ann Plast Surg 1989; 22 (4) 293-306
14 Waters LM, Pearl RM, Macaulay RM. A comparative analysis of the ability of five classes of pharmacological agents to augment skin flap survival in various models and species: an attempt to standardize skin flap research. Ann Plast Surg 1989; 23 (2) 117-122
15 Maeda M, Fukui A, Tamai S. Combined therapy with antithrombotic agents and radical scavengers for reperfusion injury of flaps. J Reconstr Microsurg 1991; 7 (3) 233-243
16 Davis RE, Wachholz JH, Jassir D, Perlyn CA, Agrama MH. Comparison of topical anti-ischemic agents in the salvage of failing random-pattern skin flaps in rats. Arch Facial Plast Surg 1999; 1 (1) 27-32
17 Forrest CR, Pang CY, Zhong AG, Kreidstein ML. Efficacy of intravenous infusion of prostacyclin (PGI2) or prostaglandin E1 (PGE1) in augmentation of skin flap blood flow and viability in the pig. Prostaglandins 1991; 41 (6) 537-558
18 Tuncer S, Ayhan S, Findikcioglu K, Ergun H, Tuncer I. Effect of systemic piracetam treatment on flap survival and vascular endothelial growth factor expression after ischemia-reperfusion injury. J Reconstr Microsurg 2011; 27 (7) 409-418
19 Grazul-Bilska AT, Johnson ML, Bilski JJ , et al. Wound healing: the role of growth factors. Drugs Today (Barc) 2003; 39 (10) 787-800
20 Debus ES, Schmidt K, Ziegler UE, Thiede A. [The role of growth factors in wound healing]. Zentralbl Chir 2000; 1: 49-55
21 Steed DL. The role of growth factors in wound healing. Surg Clin North Am 1997; 77 (3) 575-586
22 Sobiczewska E, Szmigielski S. [The role of selected cell growth factors in the wound healing process]. Przegl Lek 1997; 54 (9) 634-638
23 Greenhalgh DG. The role of growth factors in wound healing. J Trauma 1996; 41 (1) 159-167
24 Bennett NT, Schultz GS. Growth factors and wound healing: Part II. Role in normal and chronic wound healing. Am J Surg 1993; 166 (1) 74-81
25 Kiritsy CP, Lynch AB, Lynch SE. Role of growth factors in cutaneous wound healing: a review. Crit Rev Oral Biol Med 1993; 4 (5) 729-760
26 Blitstein-Willinger E. The role of growth factors in wound healing. Skin Pharmacol 1991; 4 (3) 175-182
27 Nemeth GG, Bolander ME, Martin GR. Growth factors and their role in wound and fracture healing. Prog Clin Biol Res 1988; 266: 1-17
28 Robinson CJ. Growth factors: therapeutic advances in wound healing. Ann Med 1993; 25 (6) 535-538
29 Zhang F, Waller W, Lineaweaver WC. Growth factors and flap survival. Microsurgery 2004; 24 (3) 162-167
30 Machens HG, Niedworok C, Spanholtz T, Maichle A. PDGF gene therapy enhances expression of VEGF and bFGF genes. Plast Reconstr Surg 2006; 118 (3) 820 , author reply 820–821
31 Wang XT, Liu PY, Tang JB. PDGF gene therapy enhances expression of VEGF and bFGF genes and activates the NF-kappaB gene in signal pathways in ischemic flaps. Plast Reconstr Surg 2006; 117 (1) 129-137 , discussion 138–139
32 Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267 (16) 10931-10934
33 Thurston G, Gale NW. Vascular endothelial growth factor and other signaling pathways in developmental and pathologic angiogenesis. Int J Hematol 2004; 80 (1) 7-20
34 Zhang F, Lineaweaver W. Acute and sustained effects of vascular endothelial growth factor on survival of flaps and skin grafts. Ann Plast Surg 2011; 66 (5) 581-582
35 Padubidri A, Browne Jr E. Effect of vascular endothelial growth factor (VEGF) on survival of random extension of axial pattern skin flaps in the rat. Ann Plast Surg 1996; 37 (6) 604-611
36 Wei P, Li F. [The effect of vascular endothelial cell growth factor on survival of skin flap in rats]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 1997; 11 (6) 376-378
37 Zhang F, Oswald T, Lin S , et al. Vascular endothelial growth factor (VEGF) expression and the effect of exogenous VEGF on survival of a random flap in the rat. Br J Plast Surg 2003; 56 (7) 653-659
38 Richter GT, Fan CY, Ozgursoy O, McCoy J, Vural E. Effect of vascular endothelial growth factor on skin graft survival in Sprague-Dawley rats. Arch Otolaryngol Head Neck Surg 2006; 132 (6) 637-641
39 Sun Q, Zheng Y, Ma T. [The effects of vascular endothelial growth factor on survival of reverse flow axial skin flaps]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2007; 21 (1) 44-47
40 Kryger Z, Dogan T, Zhang F , et al. Effects of VEGF administration following ischemia on survival of the gracilis muscle flap in the rat. Ann Plast Surg 1999; 43 (2) 172-178
41 Stebbins WG, Fan C, Silver L, Chun JK. Effect of VEGF on tail artery interpositional loop (TAIL) flap: a rodent model for flap prefabrication. J Reconstr Microsurg 2005; 21 (7) 477-482
42 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 (3) 314-319
43 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 (3) 1212-1216
44 Zhang F, Brooks D, Chen W, Mustain W, Chen MB, Lineaweaver WC. Improvement of venous flap survival by application of vascular endothelial growth factor in a rat model. Ann Plast Surg 2006; 56 (6) 670-673
45 Khan A, Ashrafpour H, Huang N , et al. Acute local subcutaneous VEGF165 injection for augmentation of skin flap viability: efficacy and mechanism. Am J Physiol Regul Integr Comp Physiol 2004; 287 (5) R1219-R1229
46 Miao W, Liang J, Luo S. [Comparison of effects of flap delay and vascular endothelial growth factor on the viability of the rat dorsal flap]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2006; 20 (5) 530-533
47 Tetik Menevse G, Islamoglu K, Ege Ozgentas H. Expansion of surviving skin paddle of neurocutaneous island flaps in rats by VEGF. J Reconstr Microsurg 2007; 23 (2) 99-105
48 Zhang Y, Mao JS, Wang BC , et al. [Effects on the survival of rat's abdominal axial skin flap after the combination of VEGF gene therapy and skin flap delay]. Zhonghua Zheng Xing Wai Ke Za Zhi 2008; 24 (1) 39-41
49 Kryger Z, Zhang F, Dogan T, Cheng C, Lineaweaver WC, Buncke HJ. 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 (3) 234-239
50 Wang F, Zhao M, Huang B , et al. [Subcutaneous injection of plasmid VEGF gene: a method of gene therapy to enhance the viability of random skin flap]. Zhonghua Zheng Xing Wai Ke Za Zhi 2002; 18 (3) 157-159
51 Yang LW, Zhang JX, Zeng L , et al. Vascular endothelial growth factor gene therapy with intramuscular injections of plasmid DNA enhances the survival of random pattern flaps in a rat model. Br J Plast Surg 2005; 58 (3) 339-347
52 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 (1) 55-58
53 Antonini A, Zacchigna S, Papa G, Novati F, Pascone M, Giacca M. Improved survival of rat ischemic cutaneous and musculocutaneous flaps after VEGF gene transfer. Microsurgery 2007; 27 (5) 439-445
54 Wang L, Cen Y, Xiao H. [Studies on enhancement of transverse rectus abdominis musculocutaneous flap survival by recombinant adenovirus mediated vascular endothelial growth factor 165 gene]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2005; 19 (8) 617-621
55 Giunta RE, Holzbach T, Taskov C , et al. AdVEGF165 gene transfer increases survival in overdimensioned skin flaps. J Gene Med 2005; 7 (3) 297-306
56 Michlits W, Mittermayr R, Schäfer R, Redl H, Aharinejad S. Fibrin-embedded administration of VEGF plasmid enhances skin flap survival. Wound Repair Regen 2007; 15 (3) 360-367
57 Komorowska-Timek E, Timek TA, Brevetti LS, Zhang F, Lineaweaver WC, Buncke HJ. The effect of single administration of vascular endothelial growth factor or L-arginine on necrosis and vasculature of the epigastric flap in the rat model. Br J Plast Surg 2004; 57 (4) 317-325
58 Machens HG, Salehi J, Weich H , et al. Angiogenic effects of injected VEGF165 and sVEGFR-1 (sFLT-1) in a rat flap model. J Surg Res 2003; 111 (1) 136-142
59 Li QF, Reis ED, Zhang WX, Silver L, Fallon JT, Weinberg H. Accelerated flap prefabrication with vascular endothelial growth factor. J Reconstr Microsurg 2000; 16 (1) 45-49
60 Zhang F, Richards L, Angel MF , et al. Accelerating flap maturation by vascular endothelium growth factorin a rat tube flap model. Br J Plast Surg 2002; 55 (1) 59-63
61 Huang CY, Shen ZY. [Accelerated maturation of expanded prefabricated flaps by use of vascular endothelial growth factor and basic fibroblast growth factor in rabbits]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2003; 17 (4) 293-297
62 Scalise A, Tucci MG, Lucarini G , et al. Local rh-VEGF administration enhances skin flap survival more than other types of rh-VEGF administration: a clinical, morphological and immunohistochemical study. Exp Dermatol 2004; 13 (11) 682-690
63 Zhang F, Yang F, Hu EC, Sones W, Lei M, Lineaweaver WC. Vascular endothelial growth factor gene therapy in improvement of skin paddle survival in a rat TRAM flap model. J Reconstr Microsurg 2005; 21 (6) 391-396
64 Taub PJ, Marmur JD, Zhang WX , et al. Locally administered vascular endothelial growth factor cDNA increases survival of ischemic experimental skin flaps. Plast Reconstr Surg 1998; 102 (6) 2033-2039
65 Taub PJ, Marmur JD, Zhang WX , 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 (6) 387-390
66 Xiong B, Yi CX, Guo JL, Zhang YM, Feng XL, Zhou WD. [An experimental study on the survival of the anterior abdominal skin flap after VEGF cDNA administration]. Zhonghua Zheng Xing Wai Ke Za Zhi 2003; 19 (3) 211-213
67 Xiong B, Yi CX, Chen HD , et al. [Vascular endothelial growth factor gene transfection and survival of the random skin flap in rats]. Di Yi Jun Yi Da Xue Xue Bao 2004; 24 (7) 794-797
68 Liu PY, Tong W, Liu K , et al. Liposome-mediated transfer of vascular endothelial growth factor cDNA augments survival of random-pattern skin flaps in the rat. Wound Repair Regen 2004; 12 (1) 80-85
69 Neumeister MW, Song YH, Mowlavi A, Suchy H, Mathur A. Effects of liposome-mediated gene transfer of VEGF in ischemic rat gracilis muscle. Microsurgery 2001; 21 (2) 58-62
70 Yu YS, Ye XD, Shou L. [The therapy with rhVEGF gene for ischemic TRAM flap in rats]. Zhonghua Zheng Xing Wai Ke Za Zhi 2003; 19 (5) 373-376
71 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 (2) 161-169
72 Lubiatowski P, Goldman CK, Gurunluoglu R, Carnevale K, Siemionow M. Enhancement of epigastric skin flap survival by adenovirus-mediated VEGF gene therapy. Plast Reconstr Surg 2002; 109 (6) 1986-1993
73 Cui L, Li FC, Zhang Q, Qian YL, Guan WX. Effect of adenovirus-mediated gene transfection of vascular endothelial growth factor on survival of random flaps in rats. Chin J Traumatol 2003; 6 (4) 199-204
74 Zacchigna S, Papa G, Antonini A , et al. Improved survival of ischemic cutaneous and musculocutaneous flaps after vascular endothelial growth factor gene transfer using adeno-associated virus vectors. Am J Pathol 2005; 167 (4) 981-991
75 Li FC, Cui L, Sun YX, Qian YL, Chen SS, Guan WX. [Effects of hVEGF cDNA on random skin flap via a replication-deficient adenovirus vector]. Zhonghua Zheng Xing Wai Ke Za Zhi 2004; 20 (6) 434-438
76 Gurunluoglu R, Meirer R, Shafighi M, Huemer GM, Yilmaz B, Piza-Katzer H. Gene therapy with adenovirus-mediated VEGF enhances skin flap prefabrication. Microsurgery 2005; 25 (5) 433-441
77 Mittermayr R, Morton T, Hofmann M, Helgerson S, van Griensven M, Redl H. Sustained (rh)VEGF(165) release from a sprayed fibrin biomatrix induces angiogenesis, up-regulation of endogenous VEGF-R2, and reduces ischemic flap necrosis. Wound Repair Regen 2008; 16 (4) 542-550
78 McKnight CD, Winn SR, Gong X, Hansen JE, Wax MK. Revascularization of rat fasciocutaneous flap using CROSSEAL with VEGF protein or plasmid DNA expressing VEGF. Otolaryngol Head Neck Surg 2008; 139 (2) 245-249
79 Yi CG, Guo SZ, Zhang LX , et al. [Promotion of the survival of ischemic skin flap by transplanted endothelial progenitor cells transfected with VEGF165 gene: an experimental study with mice]. Zhonghua Yi Xue Za Zhi 2005; 85 (7) 473-478
80 Lasso JM, Del Río M, García M , et al. Improving flap survival by transplantation of a VEGF-secreting endothelised scaffold during distal pedicle flap creation. J Plast Reconstr Aesthet Surg 2007; 60 (3) 279-286
81 Zheng Y, Yi C, Xia W , et al. Mesenchymal stem cells transduced by vascular endothelial growth factor gene for ischemic random skin flaps. Plast Reconstr Surg 2008; 121 (1) 59-69
82 Zheng Y, Yi CG, He LJ , et al. [Effects of mouse NIH3T3 cells transfected with VEGF gene on neovascularization of ischemic flaps]. Zhonghua Wai Ke Za Zhi 2007; 45 (3) 203-206
83 Liu PY, Liu K, Wang XT , et al. Efficacy of combination gene therapy with multiple growth factor cDNAs to enhance skin flap survival in a rat model. DNA Cell Biol 2005; 24 (11) 751-757
84 Ylä-Kotola TM, Kauhanen SC, Leivo IV, Haglund C, Tukiainen E. Vascular endothelial growth factor and its receptors are expressed in human nerve grafts. J Reconstr Microsurg 2011; 27 (3) 173-178
85 Lineaweaver WC, Lei MP, Mustain W, Oswald TM, Cui D, Zhang F. Vascular endothelium growth factor, surgical delay, and skin flap survival. Ann Surg 2004; 239 (6) 866-873 , discussion 873–875
86 Lu X, Hao J, Wang Z. [Study on mechanism of the circulation reconstructing of skin flap after early-repeated short ischemia training]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2006; 20 (7) 717-721
87 Brogi E, Wu T, Namiki A, Isner JM. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation 1994; 90 (2) 649-652
88 Detmar M, Yeo KT, Nagy JA , et al. Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol 1995; 105 (1) 44-50
89 Detmar M, Brown LF, Berse B , et al. Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptors in human skin. J Invest Dermatol 1997; 108 (3) 263-268
90 Shen H, Clauss M, Ryan J , et al. Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood 1993; 81 (10) 2767-2773
91 Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376 (6535) 66-70
92 Gille H, Kowalski J, Li B , et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 2001; 276 (5) 3222-3230
93 de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255 (5047) 989-991
94 Gerber HP, McMurtrey A, Kowalski J , et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 1998; 273 (46) 30336-30343
95 Millauer B, Wizigmann-Voos S, Schnürch H , et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993; 72 (6) 835-846
96 Chen W, Zhang F, Chen MB, Lineaweaver WC. Expression of vascular endothelial growth factor receptor-2 in the muscle flap with ischemic injury in rats. J Surg Res 2007; 140 (1) 45-49
97 Roberts DM, Kearney JB, Johnson JH, Rosenberg MP, Kumar R, Bautch VL. The vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR-1) modulates Flk-1 (VEGFR-2) signaling during blood vessel formation. Am J Pathol 2004; 164 (5) 1531-1535
98 Dunk C, Ahmed A. Vascular endothelial growth factor receptor-2-mediated mitogenesis is negatively regulated by vascular endothelial growth factor receptor-1 in tumor epithelial cells. Am J Pathol 2001; 158 (1) 265-273
99 Ahrendt G, Chickering DE, Ranieri JP. Angiogenic growth factors: A review for tissue engineering. Tissue Eng 1998; 4 (2) 117-130
100 Boontheekul T, Mooney DJ. Protein-based signaling systems in tissue engineering. Curr Opin Biotechnol 2003; 14 (5) 559-565
101 Yang R, Bunting S, Jin H. Effects of VEGF on hemodynamics and cardiac function: characterization and mechanisms. IDrugs 2000; 3 (11) 1346-1352
102 Murohara T, Horowitz JR, Silver M , et al. Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 1998; 97 (1) 99-107
103 Tucci MG, Scalise A, Lucarini G , et al. rhVEGF and experimental rat skin flaps: systemic or local administration and morphological characteristics. Int J Artif Organs 2001; 24 (10) 743-751
104 Vedder N. Flap physiology. In: Mathes SJ, Hentz VR, , eds. Plastic Surgery. Philadelphia: Saunders-Elsevier; 2005: 486-490
105 Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 1995; 108 (Pt 6) 2369-2379
106 Erdmann D, Sweis R, Wong MS , et al. Vascular endothelial growth factor expression in pig latissimus dorsi myocutaneous flaps after ischemia reperfusion injury. Plast Reconstr Surg 2003; 111 (2) 775-780
107 Erdmann D, Pippen AM, Moquin KJ , et al. Immunohistochemical identification of vascular endothelial growth factor in pig latissimus dorsi musculocutaneous flaps following ischemia-reperfusion injury. Ann Plast Surg 2004; 53 (4) 398-403
108 Roskoski Jr R. VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun 2008; 375 (3) 287-291
109 Pekala P, Marlow M, Heuvelman D, Connolly D. Regulation of hexose transport in aortic endothelial cells by vascular permeability factor and tumor necrosis factor-alpha, but not by insulin. J Biol Chem 1990; 265 (30) 18051-18054
110 O'Connor DS, Schechner JS, Adida C , et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol 2000; 156 (2) 393-398
111 Huang CY, Shen ZY. [Accelerated maturation of expanded prefabricated flaps by use of vascular endothelial growth factor and basic fibroblast growth factor in rabbits]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2003; 17 (4) 293-297
112 Pang Y, Lineaweaver WC, Lei MP , et al. Evaluation of the mechanism of vascular endothelial growth factor improvement of ischemic flap survival in rats. Plast Reconstr Surg 2003; 112 (2) 556-564
113 Zhang F, Oswald T, Holt J, Gerzenshtein J, Lei MP, Lineaweaver WC. Regulation of inducible nitric oxide synthase in ischemic preconditioning of muscle flap in a rat model. Ann Plast Surg 2004; 52 (6) 609-613
114 Topp SG, Zhang F, Chatterjee T, Lineaweaver WC. Role of nitric oxide in surgical flap survival. J Am Coll Surg 2005; 201 (4) 628-639
115 Kane AJ, Barker JE, Mitchell GM , et al. Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival. Br J Pharmacol 2001; 132 (8) 1631-1638
116 Furuta S, Vadiveloo P, Romeo-Meeuw R, Morrison W, Stewart A, Mitchell G. Early inducible nitric oxide synthase 2 (NOS 2) activity enhances ischaemic skin flap survival. Angiogenesis 2004; 7 (1) 33-43
117 Ashrafpour H, Huang N, Neligan PC , et al. Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature. Am J Physiol Heart Circ Physiol 2004; 286 (3) H946-H954
118 Zhang F, Hu EC, Gerzenshtein J, Lei MP, Lineaweaver WC. The expression of proinflammatory cytokines in the rat muscle flap with ischemia-reperfusion injury. Ann Plast Surg 2005; 54 (3) 313-317
119 Zhang F, Hu EC, Topp S, Lei M, Chen W, Lineaweaver WC. Proinflammatory cytokines gene expression in skin flaps with arterial and venous ischemia in rats. J Reconstr Microsurg 2006; 22 (8) 641-647
120 Lubiatowski P, Gurunluoglu R, Goldman CK, 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 (1) 149-159
121 Segura MM, Alba R, Bosch A, Chillón M. Advances in helper-dependent adenoviral vector research. Curr Gene Ther 2008; 8 (4) 222-235
122 Yu YS, Ye XD, Shou L. [The therapy with rhVEGF gene for ischemic TRAM flap in rats]. Zhonghua Zheng Xing Wai Ke Za Zhi 2003; 19 (5) 373-376
123 McKnight CD, Winn SR, Gong X, Hansen JE, Wax MK. Revascularization of rat fasciocutaneous flap using CROSSEAL with VEGF protein or plasmid DNA expressing VEGF. Otolaryngol Head Neck Surg 2008; 139 (2) 245-249
124 Kubota Y, Kishi K, Satoh H, Tanaka T, Nakajima H, Nakajima T. Transplanted endothelial progenitor cells augment the survival areas of rat dorsal flaps. Cell Transplant 2003; 12 (6) 647-657
125 Xie ST, Chen B, Tao K, Han JT, Wang HT. [The study on EPC originated from human umbilical cord blood promoting neovascularization in ischemic skin flap]. Zhonghua Zheng Xing Wai Ke Za Zhi 2007; 23 (3) 206-208
126 Paletta C, Pokorny J, Rumbolo P. Skin Grafts. In: Mathes S, Hentz V, , eds. Mathes Plastic Surgery. Philadelphia: WB Saunders; 2006: 263-316