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 Jignesh I Patel a,b, * , Joyce Tombran-Tink c,d , Phil G Hykin b , Zdenek J Gregor b , Ian A Cree a a Institute of Ophthalmology, London, UK b Moorfields Eye Hospital, Vitreoretinal, City Rd, EC1V 9EL, London, UK c Pharmaceutical Sciences, University of Missouri, Kansas City, MO, USA d Department of Ophthalmology, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA Received 11 July 2005; accepted in revised form 4 October 2005 Available online 1 December 2005 Abstract The aim of the study was to determine anatomical and growth factor profiles in patients with clinically significant macular oedema (CSMO) undergoing pars plana vitrectomy (PPV). Twenty patients with moderate nonproliferative diabetic retinopathy (NPDR) with persistent CSMO underwent PPV. Patients had baseline and postoperative clinical assessment including Ocular Coherence Tomography (OCT). Baseline vitreous and aqueous and serial postoperative aqueous samples were analysed for vascular endothelial growth factor-A (VEGF-A), pigment epithelium derived Factor (PEDF) and other factors (pg/ml) including hepatocyte growth factor, MMP 9, soluble flt-1 Receptor, and TGF b1 by ELISA. Vitreous from patients with full thickness macular holes (8) and proliferative diabetic retinopathy (22) were collected for comparison as controls. Vitreous VEGF-A concentration in the NPDR group was 957 pg/ml compared to 239 pg/ml in the macula hole (FTMH) control ( p!0.0001) and 596 pg/ml compared to PDR ( pZ0.006). The median diabetic vitreous PEDF concentration was 1.36 mg/ml (FTMH 2.6 mg/ml pZ0.05). In NPDR, it was higher (1.59 mg/ml) than PDR (1.27 mg/ml) pZ0.02. There were changes to the HGF, soluble flt-1 Receptor and TGF b1 concentrations in the NPDR compared to either PDR or the normal state. In CSMO, two OCT profiles were identified: dome-shaped macular elevation (Group 1) (nZ4) and diffuse-low elevation profile (Group 2) (nZ16) which also showed differences in the postoperative median aqueous VEGF concentrations despite macular volume decreasing for both. The results suggest that there is an up-regulation of VEGF in the vitreous of the diabetic eye with a reciprocal decrease in PEDF. The structural and molecular differences between the two OCT macular profiles may explain the varying response to PPV in patients with diffuse CSMO. q 2005 Elsevier Ltd. All rights reserved. Keywords: VEGF; HGF; PEDF; growth factors; vitreous; aqueous; diabetic macular oedema; OCT 1. Introduction Diabetic macular oedema is responsible for 72% of blindness due to diabetic retinopathy which is the commonest cause of visual loss in the working age population (Clark et al., 1994). The pathogenesis of diabetic macular oedema is not well understood but angiogenic growth factors (Kent et al., 2000) and vitreomacular traction (Lewis et al., 1992) are probably important. Increased retinal vascular permeability resulting from blood retinal barrier breakdown (BRB), producing macular oedema, has been recognised in human and animal models by vitreous fluorophotometric (Cunha-Vaz et al., 1975) and by immuno- histochemical (Vinores et al., 1993) methods. Growth factors found in ocular fluids may contribute to this increased vascular permeability. Exogenous Vascular Endothelial Growth Factor- A (VEGF) can produce retinal oedema in experimental animal models (Ozaki et al., 1997) by BRB breakdown of the superficial inner retinal vasculature (Qaum et al., 2001). VEGF induces damage the endothelial tight junction (Antonetti et al., 1999). Vitreous hepatocyte growth factor (HGF) is elevated in PDR (Katsura et al., 1998) and matrix metallopro- teinase 9 (MMP 9) is increased in PDR (Jin et al., 2001). Both HGF and MMP 9 can disrupt tight junctions of the endothelium (Jiang et al., 1999; Behzadian et al., 2001). Transforming Experimental Eye Research 82 (2006) 798–806 www.elsevier.com/locate/yexer 0014-4835/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.exer.2005.10.002 * Corresponding author. Jignesh I Patel, Moorfields Eye Hospital, Vitreoretinal, City Rd, EC1V 9EL, London, UK. Tel.: C44 7921710875; fax: C44 2076086862. E-mail address: jigs37@hotmail.com (J.I. Patel).