Human Ciliary Epithelium as a Source of Synthesis and Secretion of Vascular Endothelial Growth Factor in Neovascular Glaucoma

Abstract

ascular endothelial growth factor (VEGF), a secreted 46-kDa glycoprotein, is an endothelial cell-specific angiogenic and vasopermeable factor. [1][2][3][4][5][6] Vascular endothelial growth factor mediates its effects through highaffinity, cell-surface transmembrane receptors, including tyrosine kinase and fetal liver kinase 1. 6 Hypoxia regulates its gene expression in vitro and in vivo. 7,8 Expression of VEGF messenger RNA (mRNA) is induced rapidly in a variety of cultured cells, including retinal pigmented epithelium cells, by exposure to low levels of oxygen. [8][9][10] Neovascular glaucoma is a serious complication of a number of vascular disease processes that affect the eye. Diabetic retinopathy, retinal venous obstruction, and sickle cell disease are the leading etiologic factors for the development of neovascular glaucoma. 11,12 The common features in these diseases are retinal ischemia and hypoxia, which stimulate the synthesis and secretion of VEGF in the retina [13][14][15] ; subsequent diffusion of VEGF into the vitreous and aqueous humor causes intraocular neovascularization. 16 Application of panretinal photocoagulation (PRP) to an ischemic retina may induce regression of iris neovascularization in most patients. 17 In several refractory cases, contact Nd:YAG laser cyclophotocoagulation resulted in complete regression of iris neovascularization. 18 These observations prompted us to consider the involvement of nonretinal tissue in the synthesis and secretion of VEGF. Vascular endothelial growth factor was noted in the iris and ciliary body in primary uveal melanoma. 19 To search for other sites of VEGF production, we investigated the ciliary epithelium as a possible source of this growth factor with immunohistochemical analysis and in situ hybridization. Methods Tissue PreparationSixteen human enucleated eyes were investigated for the presence of VEGF with immunohistochemical analysis (VEGF protein) and in situ hybridization (VEGF mRNA). Eight human IMPORTANCE Retinal ischemia-induced upregulation of vascular endothelial growth factor (VEGF) leads to endothelial proliferation of the anterior segment, resulting in neovascular glaucoma.OBJECTIVE To investigate the ciliary epithelium as a possible source of VEGF in human eyes enucleated for intractable neovascular glaucoma. DESIGN, SETTING, AND PARTICIPANTSIn this proof-of-concept, laboratory-based study, 16 human enucleated eyes (8 with neovascular glaucoma and 8 as controls) were investigated. MAIN OUTCOMES AND MEASURESPresence of VEGF by immunohistochemical analysis (VEGF protein) and in situ hybridization (VEGF messenger RNA). RESULTSIn eyes with neovascular glaucoma, strong VEGF immunoreaction in the nonpigmented epithelial cells of the ciliary processes and in the retina was noted. In situ hybridization for VEGF messenger RNA revealed a similar pattern, with positive stain results only in eyes with neovascular glaucoma. A minimal amount of VEGF immunostaining was seen in control eyes. CONCLUSIONS AND RELEVANCEThe nonpigmented ciliary epithelium i...

The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy

“…In the eye VEGF is an important factor of ocular homeostasis [5]. It may be produced not only by vascular endothelial cells or pericytes, but also by retinal neurons and astrocytes, Müller cells, retinal pigment epithelium, and even by non-pigmented ciliary epithelium [5, 6]. Hypoxia is a proven stimulus for VEGF upregulation [5, 7].…”

Prognostic Factor Analysis of Intraocular Pressure with Neovascular Glaucoma

“…Previous studies have demonstrated increased production of several proangiogenic factors, including vascular endothelial growth factor (VEGF) [6]. In addition to the ischemic retina, nonpigmented ciliary epithelium and iris contribute to VEGF synthesis in NVG patients [7]. The created fibrovascular neovascularizational membrane promoted by these proangiogenic factors inhibits the aqueous flow and leads to an increase in IOP [4].…”

Direct Effects of Bevacizumab on Rat Conjunctival Fibroblast

“…It has been reported that Bevacizumab, a humanized monoclonal antibody that binds to all isoforms of VEGF, has shown promising results in regression of neovascularization. In clinic, successful cases were reported for Bevacizumab's application in filtering surgery [11][12][13][14][15][16]. Although, endothelial cells are the most common target cells for VEGF, others cell also presented VEGF receptors.…”

“…Especially, several groups tested Bevacizumab, humanized, non-selective monoclonal antibody against VEGF, for its application in preventing fibrosis after filtration surgery. Although their results showed promising outcome, a lot of details remain to be explored [11][12][13][14][15][16].…”