Effect of dimethyloxalylglycine on angiogenesis in Choke Ⅱ zone of cross-zone perforator flap and its mechanism_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZENG Xiuan ¹ ,  LI Meng ² , YANG Qibing ¹ , WANG Qiyuan ¹ , CHEN Yongxin ¹ , LUO Xiangli ² , LI Jidong ² , LAN Xu ²

1. The First Clinical Medical College of Gansu University of Traditional Chinese Medicine, Lanzhou Gansu, 730000, P. R. China;
2. The Fifth Department of Orthopedics, Gansu Provincial People’s Hospital, Lanzhou Gansu, 730000, P. R. China;

Corresponding author：

LI Meng, Email: lilionli@126.com

Keywords：

Cross-zone perforator flap; ChokeⅡzone; angiogenesis; dimethyloxalylglycine; rat

DOI：

10.7507/1002-1892.202107103

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Objective To study the effect of dimethyloxalylglycine (DMOG) on angiogenesis in Choke Ⅱ zone of rats cross-zone perforator flaps and its mechanism. Methods One hundred and twenty-six adult male Sprague Dawley rats were randomly divided into DMOG group, YC-1 group, and control group, with 42 rats in each group. Cross-zone perforator flap model with size of 12 cm×3 cm was made on the back of rats in the three groups. DMOG group was intraperitoneally injected with DMOG (40 mg/kg) at 1 day before operation, 2 hours before operation, and 1, 2, and 3 days after operation; YC-1 group and control group were intraperitoneally injected with YC-1 (10 mg/kg) and the same amount of normal saline at the same time points, respectively. The survival of flap was observed after operation. At 7 days after operation, the survival area of flap in each group was measured and the survival rate of flap was calculated. Flap transmittance test, gelatin-lead oxide angiography, and HE staining were used to observed the angiogenesis in the Choke Ⅱ zone of flaps in each group. Immunohistochemical staining and Western blot were used to detect the expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-1α) in Choke Ⅱ zone of flaps in each group. The expressions of VEGF and HIF-1α were also determined by ELISA at 3, 5, and 7 days. Results At 7 days after operation, there was no obvious necrosis at the distal end of the flap in DMOG group, while necrosis occurred in both the control group and YC-1 group, mainly located at the distal end. The flap survival rate of DMOG group was 90.28%±1.37%, which was significantly higher than that of YC-1 group (84.28%±1.45%) and control group (85.83%±1.60%) (P<0.05). DMOG group had more angiogenesis in Choke Ⅱ zone and the vascular structure was clear and complete. In YC-1 group and control group, the vessels in Choke Ⅱ zone was less and the vascular structure was disordered. The number of vessels was (25.56±1.29)/field in the DMOG group, which was significantly higher than that in the YC-1 group [(7.38±0.54)/field] and the control group [(14.48±0.91)/field] (P<0.05). At 3, 5, and 7 days after operation, HIF-1α and VEGF expressions in ChokeⅡzone of DMOG group were significantly higher than those in YC-1 group and control group (P<0.05). Conclusion DMOG can promote angiogenesis in Choke Ⅱ zone, accelerate the early angiogenesis of the flap, improve the microcirculation and blood supply in the potential zone of the flap, reduce the injury of flap ischemia and hypoxia, and increase the survival rate of the flap.

Citation： ZENG Xiuan, LI Meng, YANG Qibing, WANG Qiyuan, CHEN Yongxin, LUO Xiangli, LI Jidong, LAN Xu. Effect of dimethyloxalylglycine on angiogenesis in Choke Ⅱ zone of cross-zone perforator flap and its mechanism. Chinese Journal of Reparative and Reconstructive Surgery, 2022, 36(2): 224-230. doi: 10.7507/1002-1892.202107103 Copy

1.	Koshima I, Soeda S. Inferior epigastric artery skin flaps without rectus abdominis muscle. Br J Plast Surg, 1989, 42(6): 645-648.
2.	Cormack GC, Lamberty BG. Cadaver studies of correlation between vessel size and anatomical territory of cutaneous supply. Br J Plast Surg, 1986, 39(3): 300-306.
3.	Fichter AM, Ritschl LM, Robitzky LK, et al. Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model. Sci Rep, 2016, 6: 35833. doi: 10.1038/srep35833.
4.	Wang J, Ji E, Lin C, et al. Effects of bradykinin on the survival of multiterritory perforator flaps in rats. World J Surg Oncol, 2019, 17(1): 44. doi: 10.1186/s12957-019-1570-3.
5.	Taylor GI, Corlett RJ, Dhar SC, et al. The anatomical (angiosome) and clinical territories of cutaneous perforating arteries: development of the concept and designing safe flaps. Plast Reconstr Surg, 2011, 127(4): 1447-1459.
6.	Xu H, Zhang Z, Xia Y, et al. Preliminary exploration: when angiosome meets prefabricated flaps. J Reconstr Microsurg, 2016, 32(9): 683-687.
7.	Gao ZM, Lin DM, Wang Y, et al. Role of the NO/cGMP pathway in postoperative vasodilation in perforator flaps. J Reconstr Microsurg, 2015, 31(2): 107-112.
8.	李俊杰, 高自勉, 高伟阳, 等. 皮瓣延迟术对大鼠三血管体穿支皮瓣成活的影响及其机制. 中华烧伤杂志, 2014, 30(4): 337-343.
9.	裘凌峰, 楼俊盛, 杨青文, 等. 人羊膜对大鼠背部跨区皮瓣成活的影响. 中华显微外科杂志, 2017, 40(4): 358-361.
10.	严玉勇, 潘新元, 林博杰, 等. 天然水蛭素对大鼠缺血皮瓣血管生成作用的Micro-CT观察. 中国修复重建外科杂志, 2020, 34(3): 382-386.
11.	Tu Q, Liu S, Chen T, et al. Effects of adiponectin on random pattern skin flap survival in rats. Int Immunopharmacol, 2019, 76: 105875. doi:10.1016/j.intimp.2019.105875..
12.	陶先耀, 周宗伟, 杨良慧, 等. 二甲基乙二酰基甘氨酸预处理对大鼠跨区穿支皮瓣成活的影响及相关机制. 中华烧伤杂志, 2016, 32(7): 396-401.
13.	Lineaweaver WC, Zhang F. Effects of CB-VEGF-A injection in rat flap models for improved survival. Plast Reconstr Surg, 2014, 133(3): 423e-424e.
14.	习珊珊, 丁茂超, 郑俊, 等. 尾静脉注射DMOG对大鼠跨区皮瓣Choke血管区的影响. 中华显微外科杂志, 2016, 39(2): 143-147.
15.	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.
16.	Qi X, Liu Y, Ding ZY, et al. Synergistic effects of dimethyloxalylglycine and recombinant human bone morphogenetic protein-2 on repair of critical-sized bone defects in rats. Sci Rep, 2017, 7: 42820. doi: 10.1038/srep42820.
17.	Pan SL, Guh JH, Peng CY, et al. YC-1 [3-(5’-hydroxymethyl-2’-furyl)-1-benzyl indazole] inhibits endothelial cell functions induced by angiogenic factors in vitro and angiogenesis in vivo models. J Pharmacol Exp Ther, 2005, 314(1): 35-42.
18.	沈卫东, 张伟, 许庆华, 等. 3-(5’-羟甲基-2’-呋喃基)-1苯甲基引唑靶向抑制缺氧诱导因子-1α信号对大鼠非酒精性脂肪肝进程的影响. 中华肝脏病杂志, 2016, 24(10): 749-754.
19.	Kim S, Lee M, Choi YK. The role of a neurovascular signaling pathway involving hypoxia-inducible factor and Notch in the function of the central nervous system. Biomol Ther (Seoul), 2020, 28(1): 45-57.
20.	Xiao P, Zhu X, Sun J, et al. Cartilage tissue miR-214-3p regulates the TrkB/ShcB pathway paracrine VEGF to promote endothelial cell migration and angiogenesis. Bone, 2021, 151: 116034. doi: 10.1016/j.bone.2021.116034.
21.	Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab, 2018, 27(2): 281-298.

1. Koshima I, Soeda S. Inferior epigastric artery skin flaps without rectus abdominis muscle. Br J Plast Surg, 1989, 42(6): 645-648.
2. Cormack GC, Lamberty BG. Cadaver studies of correlation between vessel size and anatomical territory of cutaneous supply. Br J Plast Surg, 1986, 39(3): 300-306.
3. Fichter AM, Ritschl LM, Robitzky LK, et al. Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model. Sci Rep, 2016, 6: 35833. doi: 10.1038/srep35833.
4. Wang J, Ji E, Lin C, et al. Effects of bradykinin on the survival of multiterritory perforator flaps in rats. World J Surg Oncol, 2019, 17(1): 44. doi: 10.1186/s12957-019-1570-3.
5. Taylor GI, Corlett RJ, Dhar SC, et al. The anatomical (angiosome) and clinical territories of cutaneous perforating arteries: development of the concept and designing safe flaps. Plast Reconstr Surg, 2011, 127(4): 1447-1459.
6. Xu H, Zhang Z, Xia Y, et al. Preliminary exploration: when angiosome meets prefabricated flaps. J Reconstr Microsurg, 2016, 32(9): 683-687.
7. Gao ZM, Lin DM, Wang Y, et al. Role of the NO/cGMP pathway in postoperative vasodilation in perforator flaps. J Reconstr Microsurg, 2015, 31(2): 107-112.
8. 李俊杰, 高自勉, 高伟阳, 等. 皮瓣延迟术对大鼠三血管体穿支皮瓣成活的影响及其机制. 中华烧伤杂志, 2014, 30(4): 337-343.
9. 裘凌峰, 楼俊盛, 杨青文, 等. 人羊膜对大鼠背部跨区皮瓣成活的影响. 中华显微外科杂志, 2017, 40(4): 358-361.
10. 严玉勇, 潘新元, 林博杰, 等. 天然水蛭素对大鼠缺血皮瓣血管生成作用的Micro-CT观察. 中国修复重建外科杂志, 2020, 34(3): 382-386.
11. Tu Q, Liu S, Chen T, et al. Effects of adiponectin on random pattern skin flap survival in rats. Int Immunopharmacol, 2019, 76: 105875. doi:10.1016/j.intimp.2019.105875..
12. 陶先耀, 周宗伟, 杨良慧, 等. 二甲基乙二酰基甘氨酸预处理对大鼠跨区穿支皮瓣成活的影响及相关机制. 中华烧伤杂志, 2016, 32(7): 396-401.
13. Lineaweaver WC, Zhang F. Effects of CB-VEGF-A injection in rat flap models for improved survival. Plast Reconstr Surg, 2014, 133(3): 423e-424e.
14. 习珊珊, 丁茂超, 郑俊, 等. 尾静脉注射DMOG对大鼠跨区皮瓣Choke血管区的影响. 中华显微外科杂志, 2016, 39(2): 143-147.
15. 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.
16. Qi X, Liu Y, Ding ZY, et al. Synergistic effects of dimethyloxalylglycine and recombinant human bone morphogenetic protein-2 on repair of critical-sized bone defects in rats. Sci Rep, 2017, 7: 42820. doi: 10.1038/srep42820.
17. Pan SL, Guh JH, Peng CY, et al. YC-1 [3-(5’-hydroxymethyl-2’-furyl)-1-benzyl indazole] inhibits endothelial cell functions induced by angiogenic factors in vitro and angiogenesis in vivo models. J Pharmacol Exp Ther, 2005, 314(1): 35-42.
18. 沈卫东, 张伟, 许庆华, 等. 3-(5’-羟甲基-2’-呋喃基)-1苯甲基引唑靶向抑制缺氧诱导因子-1α信号对大鼠非酒精性脂肪肝进程的影响. 中华肝脏病杂志, 2016, 24(10): 749-754.
19. Kim S, Lee M, Choi YK. The role of a neurovascular signaling pathway involving hypoxia-inducible factor and Notch in the function of the central nervous system. Biomol Ther (Seoul), 2020, 28(1): 45-57.
20. Xiao P, Zhu X, Sun J, et al. Cartilage tissue miR-214-3p regulates the TrkB/ShcB pathway paracrine VEGF to promote endothelial cell migration and angiogenesis. Bone, 2021, 151: 116034. doi: 10.1016/j.bone.2021.116034.
21. Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab, 2018, 27(2): 281-298.

Chinese Journal of Reparative and Reconstructive Surgery

Effect of dimethyloxalylglycine on angiogenesis in Choke Ⅱ zone of cross-zone perforator flap and its mechanism

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