Vascular endothelial growth factor in eye disease

Abstract

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

The PKCβ/HuR/VEGF pathway in diabetic retinopathy

“…5). This last finding together with the observation that, in our model, VEGF mRNA shows no changes following diabetes, suggests that VEGF may be here regulated mainly at the translational level rather than at the transcriptional level as reported in literature [7], although we cannot exclude a concomitant reduction in VEGF protein degradation. This could represent a breakthrough regarding the regulation of VEGF gene expression A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 15 in diabetes, although more data are needed to strengthen this hypothesis.…”

“…VEGF (also called VEGF-A) is the major regulator of physiological and pathological angiogenesis [3], and belongs to a family that includes placental growth factor (PIGF), VEGF-B, VEGF-C,VEGF-D and VEGF-E [4,5]. In 1948 Michaelson first suggested the implication of a generic angiogenic factor in the neovascularization process occurring in retinopathy [5]; nowadays several studies stress that a key role in the development of diabetic retinopathy is indeed played by VEGF [6,7]. The expression of VEGF in diabetic retina can be regulated by different pathways, , such as Rho/Rho Kinase, ERK1/2, and Protein Kinase C (PKC) [8][9][10].…”

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

“…The production of collagen type IV and fibronectin in peripheral nerve pericytes was significantly increased after treatment with VEGF. The pro-MMP-9 proteins in peripheral nerve pericytes were upregulated after incubation with VEGF, although TIMP-1 production was not affected Each value reflects the combined densitometry data from five independent experiments and is shown as a fold increase above control **p<0.01 compared with control of the beneficial effects of anti-VEGF agents in the reduction of retinal vascular permeability [23]. We therefore hypothesised that TGF-β and VEGF signalling may contribute to the induction of basement membrane hypertrophy and disruption of the BNB.…”

“…The breakdown of the BRB occurs in patients with diabetic retinopathy [27]. Several studies have suggested that AGEs induce vasopermeability of the retina by increasing VEGF production [14,23,[28][29][30][31] and disrupt the BRB by decreasing tight junction proteins, such as occludin and ZO-1 [32]. However, the role of AGEs in diabetic neuropathy remains unclear.…”

Hypobaric hypoxia down-regulated junctional protein complex: Implications to vascular leakage

“…5,6 An increase of paracellular transport is associated with pathological conditions and disorders. [7][8][9] Endothelial paracellular transport of fluid/electrolytes/solutes is normally controlled by intercellular junctional protein complexes, including adherens junction (AJ) and tight junction (TJ). 10,11 A number of proteins are within these junctional complexes, e.g.…”