VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis.

Diabetic retinopathy (DR) is the leading cause of blindness in developed countries. DR is a common complication of diabetes, the incidence of which is rapidly increasing worldwide1. Conventionally, DR has been considered as a microcirculatory disease of the retina. However, emerging evidence has shown that retinal degeneration by apoptosis is an early event in DR. In fact, neural apoptosis is one of the most important histological features of DR2. Indeed, diabetes related apoptosis was detected in retinal ganglion cells (RGCs)1, and RGC loss has been found in both diabetic patients with no microcirculatory defect3,4,5 and STZ-induced diabetic rats6. In addition to DR, retinal apoptosis is also a potentially blinding pathology of numerous other ocular diseases, such as age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal angiomatous proliferation and macular telangiectasia1,7,8, for which there is no satisfying treatment currently. Anti-VEGF-A drugs have been used in the clinic to treat patients with DR to inhibit neovessels and edema9,10,11. However, despite of the beneficial effect, anti-VEGF-A treatment has been reported to be associated with the development of geographic atrophy (GA), the degeneration of retinal pigment epithelium (RPE) followed by the death of retinal neuronal cells. Indeed, it has been shown that within two years of anti-VEGF-A treatment, approximately 20–72% of patients with ocular neovascular diseases developed geographic atrophy (GA)12,13,14,15,16. Moreover, since patients with DR and other ocular neovascular disorders require long-term administration of anti-VEGF-A treatment, the development of GA may impose a serious problem. Thus, anti-apoptotic reagents that can protect retina from apoptosis and degeneration are highly desired. VEGF-B was discovered in 1996 as a VEGF-A homologue with high sequence homology to VEGF-A17,18. Like VEGF-A, VEGF-B binds to VEGFR1 and NP1. However, unlike VEGF-A, VEGF-B does not play a significant role in inducing blood vessel growth or vascular permeability19. Instead, VEGF-B has been shown to be a potent neuroprotective factor and an inhibitor of apoptosis for different types of neurons19,20,21,22,23. Indeed, VEGF-B is highly expressed in different types of neural tissues, such as the brain22,24, retina20, and spinal cord21. However, it remains thus far unknown whether the expressions of VEGF-B and its receptors are regulated by hyperglycemia, and whether VEGF-B could be used to inhibit hyperglycemia - or anti-VEGF-A-induced retinal apoptosis. Notwithstanding, despite the many unanswered questions regarding the function of VEGF-B in the eye, drugs that can block VEGF-B are being used to treat patients with neovascular diseases25,26. It is therefore urgent to have a better understanding of the effect of VEGF-B in hyperglycemia and after VEGF-A inhibition. To address the above questions, in this study, we used different animal models and cultured cells and investigated the effect of VEGF-B on retinal apoptosis and its expression under conditions of high glucose and VEGF-A inhibition. We found that in two retinal apoptosis models induced by diabetes or Macugen respectively, VEGF-B inhibited retinal apoptosis in different retinal layers. We also found that in vitro, the expressions of VEGF-B and its receptor VEGFR1 are upregulated by high glucose with concomitant activation of Akt and Erk. Thus, our data show that VEGF-B has a retinal protective effect and may potentially be used to treat retinal degeneration in different ocular diseases such as diabetic retinopathy and VEGF-A inhibition-induced geographic atrophy. Modulation of VEGF-B activity in the eye needs to be practiced with careful consideration.