Expression of the angiogenic mediator, angiopoietin-like 4, in the eyes of patients with proliferative sickle retinopathy

Abstract

The recent success of therapies directly targeting the angiogenic mediator, vascular endothelial growth factor (VEGF), for the treatment of proliferative diabetic retinopathy has encouraged clinicians to extend the use of anti-VEGF therapies for the treatment of another ischemic retinal vascular disease, proliferative sickle cell retinopathy (PSR), the most common cause of irreversible blindness in patients with sickle cell disease. However, results from case reports evaluating anti-VEGF therapies for PSR have been mixed. This highlights the need to identify alternative therapeutic targets for the treatment of retinal neovascularization in sickle cell patients. In this regard, angiopoietin-like 4 (ANGPTL4) is a novel angiogenic factor regulated by the transcription factor, hypoxia-inducible factor 1, the master regulator of angiogenic mediators (including VEGF) in ischemic retinal disease. In an effort to identify alternative targets for the treatment of sickle cell retinopathy, we have explored the expression of ANGPTL4 in the eyes of patients with PSR. To this end, we examined expression and localization of ANGPTL4 by immunohistochemistry in autopsy eyes from patients with known PSR (n = 5 patients). Complementary studies were performed using enzyme-linked immunosorbent assays in aqueous (n = 8; 7 patients, 2 samples from one eye of same patient) and vitreous (n = 3 patients) samples from a second group of patients with active PSR. We detected expression of ANGPTL4 in neovascular tissue and in the ischemic inner retina in PSR, but not control, eyes. We further observed elevated expression of ANGPTL4 in the aqueous and vitreous of PSR patients compared to controls. These results suggest that ANGPTL4 could contribute to the development of retinal neovascularization in sickle cell patients and could therefore be a therapeutic target for the treatment of PSR.

Sickle cell retinopathy. A focused review

“…Angiopoietin-like 4 (ANGPTL4) has been detected in neovascular tissue and in the ischemic inner retina in PSR, but not in control eyes. Its presence has been well documented in other vasoproliferative ocular condition like diabetes retinopathy, retinal vein occlusion, and age-related macular degeneration, and only recently, it was established in PSR [46]. Elevated expression of ANGPTL4 has also been observed in the aqueous and vitreous of PSR patients compared with controls [46], suggesting that it may contribute to PSR development (Fig.…”

Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

“…For instance, brain, spinal cord, and eye/retina hemangioblastoma formation is commonplace in VHL disease (94,95), owing in part to disruption of the VEGF-A (96, 97) and Notch pathways (98), among others. Dysfunction in HIF signaling is also likely involved in the aberrant vessel remodeling found in nonkidney tissues, as recent studies have implicated this pathway, and downstream mediators such as ANGPT-like 4 (ANGPTL4), in angiogenesis-related conditions including pterygia (99), uveal melanoma (100), and proliferative retinopathies (101)(102)(103). Increased insight into how angiogenesis defects lead to clinical manifestations of ocular VHL disease, such as retinal capillary hemangioblastoma (RCH) formation, will advance future therapies as well as enhance the diagnostic strategies of ophthalmological examination of VHL patients (104)(105)(106).…”

Angiopoetin-like 4 in sickle cell retinopathy

“…In their article, Yang et al [1] used the terminologies ‘in aqueous’ and ‘ in vitro ’ referring to Jee et al [5] research regarding sickle cell retinopathy (SCR). Reading Yang et al study, we understood that Jee et al [5] performed a research outside a living organism [1].…”

“…Reading Yang et al study, we understood that Jee et al [5] performed a research outside a living organism [1]. …”

“…However, Jee et al [5] studied samples of the AH and VH and noticed that the expression of ANGPTL4 was increased in patients with SCR, suggesting that ANGPTL4 might be related to the development of retinal neovascularization in SCR and could therefore be a therapeutic target for the treatment of proliferative SCR.…”