The effect of hypoxia-inducible factor-2α expressing in the neovascularization of the proliferative diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Guo Qingmin ,  Meng Xuxia , Hu Die , Zhou Xianhui , Yu Chuan

Department of Ophthalmology, Affiliated Hospital of Qingdao University, Qingdao 266500, China;
Guo Qingmin is working on the Hebei Eye Hospital, Xingtai 054001, China; Hu die is working on the Qingdao Eye Hospital, Qingdao 266071, China；Zhou Xianhui is working on the Department of Ophthalmology, Yantai YeDa Hospital, Yantai 264006, China; Yu Chuan is workng on the Wuhan Aige Eye Hospital, Wuhan 430015, China;

Corresponding author：

Meng Xuxia, Email: mengxuxia@163.com

Keywords：

Diabetic retinopathy; Retinal neovascularization; Hypoxia-inducible factor 1

DOI：

10.3760/cma.j.issn.1005-1015.2020.02.005

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Objective To observe and investigate the effect of HIF-2α in the process of neovascularization of proliferative diabetic retinopathy (PDR).Methods Retrospective clinical study. From July 2014 to July 2015, 60 eyes of 57 PDR patients diagnosed in Ophthalmology Department of Affiliated Hospital of Qingdao University were included in the study. Twenty-eight eyes of 27 patients received intravitreal injections of 0.5 mg ranibizumab (0.05 ml) at 2-7 days before surgery (ranibizumab group) and other 32 eyes of 30 patients did not (group without ranibizumab). Eighteen eyes of 18 patients with epiretinal membranes were included as controls. Pathological specimens of PDR fibrovascular membrane and premacular membrane were obtained during vitrectomy. The immunohistochemical staining and real-time PCR (RT-PCR) were used to detecting the expression of HIF-2α, Dll4 and VEGF. Kruskal-wallis test was used to compare the expression differences of correlation factors between groups. Spearman correlation analysis was used to analyze the relationship between the two variables.Results The immunohistochemical staining revealed that there were positive expression of HIF-2α, Dll4 and VEGF in all PDR membranes, regardless of the injection of the ranibizumab. The levels of HIF-2α, Dll4 and VEGF protein in the group without ranibizumab were higher than those of the ranibizumab group (t=4.36, 6.01, 4.82; P=0.000, 0.008, 0.016). RT-PCR showed that the differences of the mRNA expression of HIF-2α, Dll4 and VEGF were all statistically significant among the PDR patients and controls (H=18.81,19.60, 20.50; P=0.000, 0.000, 0.000). The expression of HIF-2α, Dll4 and VEGF in the PDR membranes was higher than that of epiretinal membranes from non-diabetic patients. In the PDR patients,the expression of HIF-2α, Dll4 and VEGF of the group without ranibizumab was higher than that of the ranibizumab group. The spearman correlation analysis showed that the expression of mRNA between HIF-2α and Dll4, HIF-2α and VEGF were both significantly correlated (r=0.95, 0.87; P＜0.05).Conclusions The expression of HIF-2α in the PDR membranes was higher than that of the controls. It is positively correlated with the expression of the DLL4 and VEGF.

Citation： Guo Qingmin, Meng Xuxia, Hu Die, Zhou Xianhui, Yu Chuan. The effect of hypoxia-inducible factor-2α expressing in the neovascularization of the proliferative diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2020, 36(2): 110-115. doi: 10.3760/cma.j.issn.1005-1015.2020.02.005 Copy

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1. Koeblitz L, Fiechtner B, Baus K, et a1. Developmental expression and hypoxic induction of hypoxia inducible transcription factors in the zebrafish[J/OL].PLoS One, 2015, 10(6): 0128938[2015-06-08]. https://doi.org/10.1371/journal.pone.0128938. DOI: 10.1371/journal.pone.0128938.
2. Schonenberger MJ, Kovacs WJ. Hypoxia signaling pathways: modulators of oxygen-related organelles[J]. Front Cell Dev Biol, 2015, 3(1): 42. DOI: 10.3389/fcell.2015.00042.
3. Lim JI, Spee C, Hinton DR. A comparison of hypoxia-inducible factor-α in surgically excised neovascular membranes of patients with diabetes compared with idiopathic epiretinal membranes in nondiabetic patients[J]. Retina, 2010, 30(9): 1472-1478. DOI: 10.1097/IAE.0b013e3181d6df09.
4. Loukovaara S, Koivunen P, Inglés M, et al. Elevated protein carbonyl and HIF-1α levels in eyes with proliferative diabetic retinopathy[J]. Acta Ophthalmol, 2014, 92(4): 323-327. DOI: 10.1111/aos.12186.
5. Sayed KM, Mahmoud AA. Heat shock protein-70 and hypoxia inducible factor-1α in type 2 diabetes mellitus patients complicated with retinopathy[J]. Acta ophthalmol, 2016, 94(5): 361-366. DOI: 10.1111/aos.12919.
6. Zhang D, Lv FL, Wang GH. Effects of HIF-1α on diabetic retinopathy angiogenesis and VEGF expression[J]. Eur Rev Med Pharmacol Sci, 2018, 22(16): 5071-5076. DOI: 10.26355/eurrev_201808_15699.
7. American Diabetes Association. Standards of medical care in diabetes--2010[J]. Diabetes Care, 2010, 33(Suppl 1): S11-61. DOI: 10.2337/dc10-S011.
8. 中华医学会眼科学会眼底病学组. 我国糖尿病视网膜病变临床诊疗指南(2014年)[J]. 中华眼科杂志, 2014, 50(11): 851-865. DOI: 10.3760/cma.j.issn.0412-4081.2014.11.014.cma.j.issn.0412-4081.2014.11.014.Chinese Ocular Fundus Diseases Society, Chinese Ophthalmological Society, Chinese Medical Association. Guidelines for clinical diagnosis and treatment of diabetic retinopathy in China[J]. Chin J Ophthalmol, 2014, 50(11): 851-865. DOI: 10.3760/cma.j.issn.0412-4081.2014.11.014.cma.j.issn.0412-4081.2014.11.014.
9. Skuli N, Majmundar AJ, Krock BL, et a1. Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes[J]. J Clin Invest, 2012, 122(4): 1427-1443. DOI: 10.1172/JCI57322.
10. Hamidian A, von Stedingk K, Thoren MM, et a1. Differential regulation of HIF-1 alpha and HIF-2 alpha in neuroblastoma: estrogen-related receptor alpha(ERR alpha) regulates HIF2A transcription and correlates to poor outcome[J]. Biochem Biophys Res Commun, 2015, 461(3): 560-567. DOI: 10.1016/j.bbrc.2015.04.083.
11. 刘卫青, 代荣钦, 郭志松, 等. 缺氧诱导因子-1α、缺氧诱导因子-2α在非小细胞肺癌肿瘤组织中的表达及临床意义[J]. 中华实验外科杂志, 2015, 32(11): 2854-2856. DOI: 10.3760/cma.j.issn.1001-9030.2015.11.072.Liu WQ, Dai RQ, Guo ZS, et al. Expression and clinical significance of hypoxia inducible factor-1α and hypoxia inducible factor-2α in non-small cell lung cancer tissues[J]. Chin J Exp Surg, 2015, 32(11): 2854-2856. DOI: 10.3760/cma.j.issn.1001-9030.2015.11.072.
12. Altun M, Zhao B, Velasco K, et al. Ubiquitin-specific protease 19 (USP19) regulates hypoxia- inducible factor 1α (HIF-1α) during hypoxia[J]. J Biol Chem, 2012, 287(3): 1962-1969. DOI: 10.1074/jbc.M111.305615.
13. Ratter A, Williams J, Nathans J. Roles of HIFs and VEGF in angiogenesis in the retina and brain[J]. J Clin Invest, 2019, 130: 3807-3820. DOI: 10.1172/JCI126655.
14. Duan LJ, Fong GH. Developmental vascular pruning in neonatal mouse retinas is programmed by the astrocytic oxygen-sensing mechanism[J/OL]. Development, 2019, 146(8): 175117[2019-04-17]. https://dev.biologists.org/content/146/8/dev175117.long. DOI:10.1242/dev.175117.
15. Befani C, Liakos P. The role of hypoxia-inducible factor-2 alpha in angiogenesis[J]. J Cell Physiol, 2018, 233(12): 9087-9098. DOI: 10.1002/jcp.26805.
16. Hashimoto T, Shibasaki F. Hypoxia-inducible factor as an angiogenic master switch[J]. Front Pediatr, 2015, 3: 33. DOI: 10.3389/fped.2015.00033.
17. Zhao L, Borikova AL, Ben-Yair R, et al. Notch signaling regulates cardiomyocyte proliferation during zebra fish heart regeneration[J]. Proc Natl Acad Sci USA, 2014, 111(4): 1403-1408. DOI: 10.1073/pnas.1311705111.
18. de Bock K, Georgiadou M, Carmeliet P. Role of endothelial cell metabolism in vessel prouting[J]. Cell Metab, 2013, 18(5): 634-647. DOI: 10.1016/j.cmet.2013.08.001.
19. Zhao J, Du F, Shen G, et a1. The role of hypoxia-inducible factor-2 in digestive system cancers[J]. Cell Death Dis, 2015, 6(1): 1600. DOI: 10.1038/cddis.2014.565.
20. Wei K, Piecewicz SM, Mcginnis LM, et a1. A liver HIF-2 Alpha-IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition[J]. Nat Med, 2013, 19(10): 1331-1338. DOI: 10.1038/nm.3295.

Chinese Journal of Ocular Fundus Diseases

The effect of hypoxia-inducible factor-2α expressing in the neovascularization of the proliferative diabetic retinopathy

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