EFFECT OF PHARMACOLOGIC DELAY WITH PIOGLITAZONE ON EXTENDED PERFORATOR FLAP SURVIVAL IN A RAT MODEL_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIZhefeng ,  GAOWeiyang , CHENShiyi , LIJunjie , YANHede , LIZhijie , LINDingsheng

Department of Hand and Plastic Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou Zhejiang, 325027, P. R. China;

Corresponding author：

GAOWeiyang, Email: wygao1@163.com

Keywords：

Peroxisome proliferator-activated receptor γ agonist; Pioglitazone; Pharmacologic delay; Extended perforator flap; choke vessel; Rat

DOI：

10.7507/1002-1892.20140155

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Objective To investigate the effect of pharmacologic delay with pioglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, on extended perforator flap survival in a rat model. Methods Seventy male Sprague Dawley rats, weighing 250-300 g, were randomly divided into control group (n=35) and experimental group (n=35). A three-territory flap was made, including two choke zones. Pioglitazone was dissolved in 1.5 mL saline. Oral doses of pioglitazone[10 mg/(kg·d)] was given by gavaged for 5 days in the experimental group, while the same volume of saline was given in the control group at same time point. After 7 days, the flap survival area was measured and angiographic diagnosis was made. The tissue samples were harvested from choke zone Ⅱ for histological study and vascular endothelial growth factor (VEGF) expression detection by immunohistochemical staining. The content of nitric oxide (NO) in choke zones I and Ⅱ was measured at immediate, 1, 3, 5, and 7 days after operation. Results The flap general change of 2 groups was similar. Varying degrees of necrosis occurred with the extension of time in 2 groups. At 7 days after operation, the flap survival rate was 87.73%±3.25% in the experimental group and 76.07%±2.92% in the control group, showing a significant difference (t=-10.338, P=0.000). The number of true anastomosis in choke zones I and Ⅱ was 5.40±1.14 and 3.00±0.71 in the experimental group, and was 3.20±0.84 and 0.80±0.84 in the control group respectively, showing significant differences between the 2 groups (t=-3.479, P=0.008;t=-4.491, P=0.002). The microvessel density and the expression of VEGF in choke zone Ⅱ of experimental group were (33.16±7.73)/mm² and 4 368.80±458.23, respectively, which were significantly higher than those of control group[(23.29±5.91)/mm² and 2 241.24±554.43] (t=5.073, P=0.000;t=-14.789, P=0.000). The content of NO in the experimental group were significantly higher than those in the control group at other time points (P<0.05) except for at immediate after operation. Conclusion Pharmacologic delay with pioglitazone can improve extended perforator flap viability through increasing ischemia-induced angiogenesis and choke vessels vasodilation in rat models.

Citation： LIZhefeng, GAOWeiyang, CHENShiyi, LIJunjie, YANHede, LIZhijie, LINDingsheng. EFFECT OF PHARMACOLOGIC DELAY WITH PIOGLITAZONE ON EXTENDED PERFORATOR FLAP SURVIVAL IN A RAT MODEL. Chinese Journal of Reparative and Reconstructive Surgery, 2014, 28(6): 701-706. doi: 10.7507/1002-1892.20140155 Copy

1.	Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body:experimental study and clinical applications. Br J Plast Surg, 1987, 40(2):113-141.
2.	Cormack GC, Lamberty BG. A classification of fascio-cutaneous flaps according to their patterns of vascularisation. Br J Plast Surg, 1984, 37(1):80-87.
3.	Dhar SC, Taylor GI. The delay phenomenon:the story unfolds. Plast Reconstr Surg, 1999, 104(7):2079-2091.
4.	Morris SF, Taylor GI. The time sequence of the delay phenomenon:when is a surgical delay effective? An experimental study. Plast Reconstr Surg, 1995, 95(3):526-533.
5.	Coşkunfirat OK, Oksar HS, Ozgentaş HE. Effect of the delay phenomenon in the rat single-perforator-based abdominal skin flap model. Ann Plast Surg, 2000, 45(1):42-47.
6.	Gözü A, Poda M, Taşkin EI, et al. Pretreatment with octreotide modulates iNOS gene expression, mimics surgical delay, and improves flap survival. Ann Plast Surg, 2010, 65(2):245-249.
7.	Findikcioglu F, Findikcioglu K, Yavuzer R, et al. Effect of preoperative subcutaneous platelet-rich plasma and fibrin glue application on skin flap survival. Aesthetic Plast Surg, 2012, 36(5):1246-1253.
8.	Reel B, Guzeloglu M, Bagriyanik A, et al. The effects of PPAR-γ agonist pioglitazone on renal ischemia/reperfusion injury in rats. J Surg Res, 2013, 182(1):176-184.
9.	Somi MH, Hajipour B, Asl NA, et al. Pioglitazone attenuates ischemia/reperfusion-induced liver injury in rats. Transplant Proc, 2009, 41(10):4105-4109.
10.	Huang PH, Sata M, Nishimatsu H, et al. Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice. Biomed Pharmacother, 2008, 62(1):46-52.
11.	Nagahama R, Matoba T, Nakano K, et al. Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia. Arterioscler Thromb Vasc Biol, 2012, 32(10):2427-2434.
12.	Miyamoto S, Minabe T, Harii K. Effect of recipient arterial blood inflow on free flap survival area. Plast Reconstr Surg, 2008, 121(2):505-513.
13.	Ahmed LA, Salem HA, Attia AS, et al. Pharmacological preconditioning with nicorandil and pioglitazone attenuates myocardial ischemia/reperfusion injury in rats. Eur J Pharmacol, 2011, 663(1-3):51-58.
14.	林丁盛, 郑鑫, 李志杰, 等. 水蛭素对大鼠随意型皮瓣存活的影响. 中华整形外科, 2011, 27(1):35-39.
15.	Yang M, Angel MF, Pang Y, et al. Expression of inducible nitric oxide synthase in muscle flaps treated with ischemic postconditioning. Hand (N Y), 2012, 7(3):297-302.
16.	Baynosa RC, Naig AL, Murphy PS, et al. The effect of hyperbaric oxygen on nitric oxide synthase activity and expression in ischemia-reperfusion injury. J Surg Res, 2013, 183(1):355-361.
17.	Gribbe O, Samuelson UE, Wiklund NP. Effects of nitric oxide synthase inhibition on blood flow and survival in experimental skin flaps. J Plast Reconstr Aesthet Surg, 2007, 60(3):287-293.
18.	McDonald WS, Lo TP Jr, Thurmond M, et al. Role of nitric oxide in skin flap delay. Plast Reconstr Surg, 2004, 113(3):927-931.
19.	Polikandriotis JA, Mazzella LJ, Rupnow HL, et al. Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol, 2005, 25(9):1810-1816.
20.	Zhuang Y, Hu S, Wu D, et al. A novel in vivo technique for observations of choke vessels in a rat skin flap model. Plast Reconstr Surg, 2012, 130(2):308-317.
21.	Fang T, Lineaweaver WC, Chen MB, et al. Effects of vascular endothelial growth factor on survival of surgical flaps:a review of experimental studies. J Reconstr Microsurg, 2014, 30(1):1-13.
22.	鲁晓波, 郝建伟, 王兆强. 早期反复短时缺血训练对皮瓣成活的影响及其机制研究. 中国修复重建外科杂志, 2006, 20(7):717-721.
23.	王立夫, 岑瑛, 肖海涛. 重组腺病毒介导的血管内皮生长因子165基因增强大鼠横形腹直肌肌皮瓣活力的研究. 中国修复重建外科杂志, 2005, 19(8):617-621.
24.	Xiao-Xiao T, Sen-Min W, Ding-Sheng L. Effects of vinpocetine on random skin flap survival in rats. J Reconstr Microsurg, 2013, 29(6):393-398.
25.	Yamakawa K, Hosoi M, Koyama H, et al. Peroxisome proliferator-activated receptor-gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells. Biochem Biophys Res Commun, 2000, 271(3):571-574.
26.	Morris SF, Taylor GI. Predicting the survival of experimental skin flaps with a knowledge of the vascular architecture. Plast Reconstr Surg, 1993, 92(7):1352-1361.

1. Taylor GI, Palmer JH. The vascular territories (angiosomes) of the body:experimental study and clinical applications. Br J Plast Surg, 1987, 40(2):113-141.
2. Cormack GC, Lamberty BG. A classification of fascio-cutaneous flaps according to their patterns of vascularisation. Br J Plast Surg, 1984, 37(1):80-87.
3. Dhar SC, Taylor GI. The delay phenomenon:the story unfolds. Plast Reconstr Surg, 1999, 104(7):2079-2091.
4. Morris SF, Taylor GI. The time sequence of the delay phenomenon:when is a surgical delay effective? An experimental study. Plast Reconstr Surg, 1995, 95(3):526-533.
5. Coşkunfirat OK, Oksar HS, Ozgentaş HE. Effect of the delay phenomenon in the rat single-perforator-based abdominal skin flap model. Ann Plast Surg, 2000, 45(1):42-47.
6. Gözü A, Poda M, Taşkin EI, et al. Pretreatment with octreotide modulates iNOS gene expression, mimics surgical delay, and improves flap survival. Ann Plast Surg, 2010, 65(2):245-249.
7. Findikcioglu F, Findikcioglu K, Yavuzer R, et al. Effect of preoperative subcutaneous platelet-rich plasma and fibrin glue application on skin flap survival. Aesthetic Plast Surg, 2012, 36(5):1246-1253.
8. Reel B, Guzeloglu M, Bagriyanik A, et al. The effects of PPAR-γ agonist pioglitazone on renal ischemia/reperfusion injury in rats. J Surg Res, 2013, 182(1):176-184.
9. Somi MH, Hajipour B, Asl NA, et al. Pioglitazone attenuates ischemia/reperfusion-induced liver injury in rats. Transplant Proc, 2009, 41(10):4105-4109.
10. Huang PH, Sata M, Nishimatsu H, et al. Pioglitazone ameliorates endothelial dysfunction and restores ischemia-induced angiogenesis in diabetic mice. Biomed Pharmacother, 2008, 62(1):46-52.
11. Nagahama R, Matoba T, Nakano K, et al. Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia. Arterioscler Thromb Vasc Biol, 2012, 32(10):2427-2434.
12. Miyamoto S, Minabe T, Harii K. Effect of recipient arterial blood inflow on free flap survival area. Plast Reconstr Surg, 2008, 121(2):505-513.
13. Ahmed LA, Salem HA, Attia AS, et al. Pharmacological preconditioning with nicorandil and pioglitazone attenuates myocardial ischemia/reperfusion injury in rats. Eur J Pharmacol, 2011, 663(1-3):51-58.
14. 林丁盛, 郑鑫, 李志杰, 等. 水蛭素对大鼠随意型皮瓣存活的影响. 中华整形外科, 2011, 27(1):35-39.
15. Yang M, Angel MF, Pang Y, et al. Expression of inducible nitric oxide synthase in muscle flaps treated with ischemic postconditioning. Hand (N Y), 2012, 7(3):297-302.
16. Baynosa RC, Naig AL, Murphy PS, et al. The effect of hyperbaric oxygen on nitric oxide synthase activity and expression in ischemia-reperfusion injury. J Surg Res, 2013, 183(1):355-361.
17. Gribbe O, Samuelson UE, Wiklund NP. Effects of nitric oxide synthase inhibition on blood flow and survival in experimental skin flaps. J Plast Reconstr Aesthet Surg, 2007, 60(3):287-293.
18. McDonald WS, Lo TP Jr, Thurmond M, et al. Role of nitric oxide in skin flap delay. Plast Reconstr Surg, 2004, 113(3):927-931.
19. Polikandriotis JA, Mazzella LJ, Rupnow HL, et al. Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol, 2005, 25(9):1810-1816.
20. Zhuang Y, Hu S, Wu D, et al. A novel in vivo technique for observations of choke vessels in a rat skin flap model. Plast Reconstr Surg, 2012, 130(2):308-317.
21. Fang T, Lineaweaver WC, Chen MB, et al. Effects of vascular endothelial growth factor on survival of surgical flaps:a review of experimental studies. J Reconstr Microsurg, 2014, 30(1):1-13.
22. 鲁晓波, 郝建伟, 王兆强. 早期反复短时缺血训练对皮瓣成活的影响及其机制研究. 中国修复重建外科杂志, 2006, 20(7):717-721.
23. 王立夫, 岑瑛, 肖海涛. 重组腺病毒介导的血管内皮生长因子165基因增强大鼠横形腹直肌肌皮瓣活力的研究. 中国修复重建外科杂志, 2005, 19(8):617-621.
24. Xiao-Xiao T, Sen-Min W, Ding-Sheng L. Effects of vinpocetine on random skin flap survival in rats. J Reconstr Microsurg, 2013, 29(6):393-398.
25. Yamakawa K, Hosoi M, Koyama H, et al. Peroxisome proliferator-activated receptor-gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells. Biochem Biophys Res Commun, 2000, 271(3):571-574.
26. Morris SF, Taylor GI. Predicting the survival of experimental skin flaps with a knowledge of the vascular architecture. Plast Reconstr Surg, 1993, 92(7):1352-1361.

Chinese Journal of Reparative and Reconstructive Surgery

EFFECT OF PHARMACOLOGIC DELAY WITH PIOGLITAZONE ON EXTENDED PERFORATOR FLAP SURVIVAL IN A RAT MODEL

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