VEGF₁₆₄Is Proinflammatory in the Diabetic Retina

Abstract

On an equimolar basis, VEGF(164) is at least twice as potent as VEGF(120) at inducing ICAM-1-mediated retinal leukostasis and BRB breakdown in vivo. The inhibition of diabetic retinal leukostasis and BRB breakdown with EYE001 in early and established diabetes indicates that VEGF(164) is an important isoform in the pathogenesis of early diabetic retinopathy.

Vascular endothelial growth factor in eye disease

“…The role of VEGF in causing inflammation during diabetic retinopathy has also been demonstrated by studies showing that increases in VEGF expression are correlated with increased levels of ICAM-1 immunoreactivity and leukostasis in the retinas of diabetic animals (Hammes et al, 1998;Joussen et al, 2001;Joussen et al, 2002;Miyamoto et al, 1999;Murata et al, 1996;Qaum et al, 2001). The VEGF 165 isoform is thought to be critically involved in the retinal vascular inflammatory response to diabetes in that isoform-specific blockade of VEGF 165 suppresses leukostasis and restores normal blood-retinal barrier function in diabetic rats (Ishida et al, 2003). This concept is further supported by data showing that intravitreal injection of VEGF 165 induces expression of ICAM-1 in the retinal vasculature of mice (Lu et al, 1999) and increases ICAM-1 levels and leukostasis in rats (Ishida et al, 2003).…”

“…The VEGF 165 isoform is thought to be critically involved in the retinal vascular inflammatory response to diabetes in that isoform-specific blockade of VEGF 165 suppresses leukostasis and restores normal blood-retinal barrier function in diabetic rats (Ishida et al, 2003). This concept is further supported by data showing that intravitreal injection of VEGF 165 induces expression of ICAM-1 in the retinal vasculature of mice (Lu et al, 1999) and increases ICAM-1 levels and leukostasis in rats (Ishida et al, 2003).…”

“…Studies in diabetic animal models have shown that retinal vascular alterations resembling background diabetic retinopathy are associated with increases in retinal VEGF levels and increased expression of VEGFR2 (Gilbert et al, 1998;Hammes et al, 1998). Furthermore, blocking VEGF function can prevent diabetes-induced permeability increases in both patients (Avery et al, 2006;Haritoglou et al, 2006;Jorge et al, 2006;Starita et al, 2007) and animal models (Ideno et al, 2007;Ishida et al, 2003;Qaum et al, 2001), implying a direct role for VEGF in this pathology.…”

“…IRES-dependent production of alternatively spliced VEGF isoforms may also contribute to the pathological effects of VEGF in the diabetic retina. 165 is a potent inducer of retinal vascular inflammation as well as a mediator of neuronal survival, whereas VEGF 121 promotes neuronal survival, but does not induce vascular inflammation (Ishida et al, 2003;Nishijima et al, 2007). Decreased levels of the dominant negative splice variant VEGF 165b were found in vitreous samples from patients with diabetic retinopathy, suggesting that a molecular switch between the VEGF 165 and VEGF 165b could be involved the development of diabetic retinopathy (Perrin et al, 2005).…”

“…The permeability defect has been correlated with increased ocular levels of VEGF in clinical specimens and experimental animals (Adamis et al, 1994;Aiello et al, 1994;El-Remessy, 2003b;Qaum et al, 2001;Takeda et al, 2001). Studies with a variety of VEGF blocking strategies have demonstrated the role of VEGF in the permeability response of diabetic animals (Ideno et al, 2007;Ishida et al, 2003;Qaum et al, 2001). Clinical trials in patients with diabetic macular edema have shown beneficial effects of anti-VEGF agents in reducing retinal vascular permeability as assessed by fluorescein angiography and decreasing macular edema as shown by optical coherence tomography (Avery et al, 2006;Haritoglou et al, 2006;Jorge et al, 2006;Starita et al, 2007).…”