Syed Shoaib AHMED, Abrar Ahmed MALIK, Masoom KHAN, Roquyya GUL, Tayyaba Gul MALIK, Muhammad KHALIL

Effect of intravitreal bevacizumab on macular thickness: exploring serum and vitreous proangiogenic biomarkers in patients with diabetic macular edema

Background/aim: This study evaluates diabetic macular-edema (DME) patients for the effect of intravitreal bevacizumab (IVB)injection on macular thickness and proangiogenic biomarkers in serum and vitreous.Materials and methods: Forty DME patients were analyzed for macular thickness (MT). Twelve proangiogenic biomarkers in serumand vitreous were analyzed before and after IVB.Results: Significant decrease in MT with vitreal vascular endothelial growth factor-A (VEGF-A) was observed as expected after IVB,while serum VEGF-A did not follow a decreasing trend in contrast to VEGF-C, which decreased both in serum and vitreous. Othervitreal factors like bone morphogenetic protein-9 (BMP9) and fibroblast growth factor (FGF) were also significantly decreased, whileendothelial growth factor (EGF) increased following IVB. Before IVB, significant negative correlations were vitreous BMP9 with serumFGF, vitreous human growth factor (HGF) and interleukin-8 (IL-8) with serum endothelin, and vitreous and serum FGF and serumplacental growth factor (PLGF) with EGF. After IVB, negative correlations in serum vs. vitreous were found for both HGF and PLGFwith BMP9, and angiopoietin with FGF. Cube average thickness was negatively correlated with serum FGF and positively correlatedwith vitreous PLGF and endothelin.Conclusion: Vascular endothelial growth factors are not the only factors that cause macular edema in diabetic patients. The effect of IVBon different proangiogenic biomarkers indicated a complex interplay of other factors in DME.

PDF

___

Biomarkers Definition Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Therapeutics 2001; 69: 89-95.
World Health Organization, International Programme on Chemical Safety. Biomarkers in Risk Assessment: Validity and Validation. Geneva, Switzerland: World Health Organization; 2001.
Bostrom KI, Jumabay M, Matveyenko A, Nicholas SB, Yao Y. Activation of vascular bone morphogenetic protein signaling in diabetes mellitus. Circ Res 2011; 108: 446-457.
Li W, Salmon RM, Jiang H, Morrell NW. Regulation of the ALK1 ligands, BMP9 and BMP10. Biochem Soc Trans 2016; 44: 1135- 1141.
Liu JJ, Foo JP, Liu S, Lim SC. The role of fibroblast growth factor 21 in diabetes and its complications: a review from clinical perspective. Diabetes Res Clin Pract 2015; 108: 382-389.
Kaga T, Kawano H, Sakaguchi M, Nakazawa T, Taniyama Y, Morishita R. Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor. Vascul Pharmacol 2012; 57: 3-9.
Cuevas P, Outeirino LA, Angulo J, Gimenez-Gallego G. Chronic cystoid macular oedema treated with intravitreal dobesilate. BMJ Case Rep 2012; 2012: bcr2012006376.
dell’Omo R, Semeraro F, Bamonte G, Cifariello F, Romano MR, Costagliola C. Vitreous mediators in retinal hypoxic diseases. Mediators Inflamm 2013; 2013: 935301.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676.
Engerman RL, Kern TS. Hyperglycemia and development of glomerular pathology: diabetes compared with galactosemia. Kidney Int 1989; 36: 41-45.
Engerman RL, Kern TS. Aldose reductase inhibition fails to prevent retinopathy in diabetic and galactosemic dogs. Diabetes 1993; 42: 820-825.
Hohman TC, Nishimura C, Robison WG Jr. Aldose reductase and polyol in cultured pericytes of human retinal capillaries. Exp Eye Res 1989; 48: 55-60.
Malik TG, Khalil M, Gul R, Ahmad SS, Munawar S. Serum versus vitreous VEGF A and central macular thickness in diabetic macular edema and the effect of intra-vitreal bevacizumab on these variables. Pak J Ophthalmol 2016; 32: 78-83.
Christinger HW, Fuh G, de Vos AM, Wiesmann C. The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1. J Biol Chem 2004; 279: 10382-10388.
Miyamoto N, de Kozak Y, Jeanny JC, Glotin A, Mascarelli F, Massin P, BenEzra D, Behar-Cohen F. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia 2007; 50: 461-470.
Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 2007; 38: 258-268.
Shih SC, Ju M, Liu N, Smith LE. Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. J Clin Invest 2003; 112: 50-57.
Cao R, Xue Y, Hedlund EM, Zhong Z, Tritsaris K, Tondelli B, Lucchini F, Zhu Z, Dissing S, Cao Y. VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. P Natl Acad Sci USA 2010;107: 856-861.
Kowalczuk L, Touchard E, Omri S, Jonet L, Klein C, Valamanes F, Berdugo M, Bigey P, Massin P, Jeanny JC et al. Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy. PLoS One 2011; 6: e17462.
Fredj-Reygrobellet D, Baudouin C, Negre F, Caruelle JP, Gastaud P, Lapalus P. Acidic FGF and other growth factors in preretinal membranes from patients with diabetic retinopathy and proliferative vitreoretinopathy. Ophthalmic Res 1991; 23: 154-161.
Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: Implications for structural differences in macular profiles. Exp Eye Res 2006; 82: 798-806.
Canton A, Burgos R, Hernandez C, Mateo C, Segura RM, Mesa J, Simo R. Hepatocyte growth factor in vitreous and serum from patients with proliferative diabetic retinopathy. Br J Ophthalmol 2000; 84: 732-735.
Yoshida A, Yoshida S, Khalil AK, Ishibashi T, Inomata H. Role of NF-kappaB-mediated interleukin-8 expression in intraocular neovascularization. Invest Ophthalmol Vis Sci 1998; 39: 1097- 1106.
Ghasemi H, Ghazanfari T, Yaraee R, Faghihzadeh S, Hassan ZM. Roles of IL-8 in ocular inflammations: a review. Ocul Immunol Inflamm 2011; 19: 401-412.
Murugeswari P, Shukla D, Rajendran A, Kim R, Namperumalsamy P, Muthukkaruppan V. Proinflammatory cytokines and angiogenic and anti-angiogenic factors in vitreous of patients with proliferative diabetic retinopathy and Eales’ disease. Retina 2008; 28: 817-824.
Lee TH, Avraham H, Lee SH, Avraham S. Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells. J Biol Chem 2002; 277: 10445-10451.
Arsovska MG. Correlation of diabetic maculopathy and level of diabetic retinopathy. Prilozi 2006; 27: 139-150.
Khuu LA, Tayyari F, Sivak JM, Flanagan JG, Singer S, Brent MH, Huang D, Tan O, Hudson C. Aqueous humor endothelin-1 and total retinal blood flow in patients with non-proliferative diabetic retinopathy. Eye 2017; 31: 1443-1450.
Glasow A, Kiess W, Anderegg U, Berthold A, Bottner A, Kratzsch J. Expression of leptin (Ob) and leptin receptor (Ob-R) in human fibroblasts: regulation of leptin secretion by insulin. J Clin Endocrinol Metab 2001; 86: 4472-4479.
Gariano RF, Nath AK, D’Amico DJ, Lee T, Sierra-Honigmann MR. Elevation of vitreous leptin in diabetic retinopathy and retinal detachment. Invest Ophthalmol Vis Sci 2000; 41: 3576- 3581.
Sari R, Balci MK, Apaydin C. The relationship between plasma leptin levels and chronic complication in patients with type 2 diabetes mellitus. Metab Syndr Relat Disord 2010; 8: 499-503.
Hansen J, Rinnov A, Krogh-Madsen R, Fischer CP, Andreasen AS, Berg RM, Moller K, Pedersen BK, Plomgaard P. Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation. Diabetes Metab Res Rev 2013; 29: 463-472.
Patel JI, Hykin PG, Gregor ZJ, Boulton M, Cree IA. Angiopoietin concentrations in diabetic retinopathy. Br J Ophthalmol 2005; 89: 480-483.
Rangasamy S, Srinivasan R, Maestas J, McGuire PG, Das A. A potential role for angiopoietin 2 in the regulation of the bloodretinal barrier in diabetic retinopathy. Invest Ophthalmol Vis Sci 2011; 52: 3784-3791.
Campochiaro PA, Hafiz G, Mir TA, Scott AW, Zimmer-Galler I, Shah SM, Wenick AS, Brady CJ, Han I, He L et al. Propermeability factors in diabetic macular edema; the diabetic macular edema treated with Ozurdex trial. Am J Ophthalmol 2016; 168: 13-23.