*4.4.1.6 Connective tissue growth factor*

Connective tissue growth factor, also known as CCN2, is a cysteine-rich matricellular protein forms part of control on biological processes, such as cell proliferation, differentiation, adhesion and angiogenesis, as well as multiple pathologies, such as tumour development and tissue fibrosis [59]. Possible role of CTGF, CD105, and gelatinase B in the pathogenesis of proliferative vitreo-retinal disorders has been suggested by various studies [60]. It has been see that both CTGF and VEGF levels are elevated in PDR patients and CTGF could help in development of proliferative membranes in PDR though plays no role in retinal neovascularization [61].

#### *4.4.1.7 Hepatocyte growth factor*

Its has been seen that HCG and its receptor unit control motility, growth and morphogenesis of various cell types and possess angiogenic activity [62]. Data indicates that HGF is a pro-permeability, pro-inflammatory, and pro-angiogenic factor and along with its activator is found increased in ischemic retina providing support for a potential role of HGF in macular edema and in ischemic retinopathies such as diabetic retinopathy [63]. Elevated levels of HCG in aqueous have been found to be directly related to degree of PDR [64].

#### *4.4.1.8 Stem cell factor*

EPO is a glycoprotein which is multifunctional, produced in foetal liver and adult kidney when exposed to hypoxic conditions [65]. It possess antiinflammatory, antioxidant, pro-angiogenic properties [66–68]. Some studies have also documented neuro-protective and anti-apoptotic properties [69, 70]. The mechanisms controlling the expression of the gene encoding for the hormone erythropoietin (EPO) are exemplary for oxygen-regulated gene expression. In humans and other mammals, hypoxia modulates EPO levels by increasing expression of the EPO gene [71]. Expression of EPO is mediated by HIF-1α which simultaneously stimulates VEGF secretion [72]. The hormone erythropoietin (EPO) maintains red blood cell mass by promoting the survival, proliferation and differentiation of erythrocytic progenitors. Circulating EPO originates mainly from fibroblasts in the renal cortex. EPO production is controlled at the transcriptional level. Hypoxia attenuates the inhibition of the EPO promoter by GATA-2 [73]. In patients with PDR, both EPO and VEGF are up-regulated into the vitreous each acting independently [74]. It has been seen that inhibition of EPO or VEGF leads to suppression of retinal neovascularization, results are best when both are suppressed together and in vitro inhibition of EPO leads to attenuation of endothelial cell proliferation in PDR [75].

#### *4.4.2 Transcription factors*
