A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics

Abstract

Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases. The pathogenesis of RVO is multifactorial and involves a complex interplay among a variety of vascular and inflammatory mediators. Many cytokines, chemokines, growth factors, and cell adhesion molecules have been reported to be implicated. Treatments for RVO are directed at the management of underlying risk factors and vision-threatening complications, including macula edema (ME) and neovascularization. Intravitreal anti-VEGF agents are currently considered as the first-line treatment for ME secondary to RVO (RVO-ME), but a substantial proportion of patients responded insufficiently to anti-VEGF agents. Since RVO-ME refractory to anti-VEGF agents generally responds to corticosteroids and its visual outcome is negatively correlated to disease duration, prediction of treatment response at baseline in RVO-ME may significantly improve both cost-effectiveness and visual prognosis. Several bioactive molecules in the aqueous humor were found to be associated with disease status in RVO. This review aims to present a comprehensive review of intraocular biomolecules reported in RVO, including VEGF, IL-6, IL-8, MCP-1, sICAM-1, IL-12, IL-13, sVEGFR-1, sVEGFR-2, PDGF-AA, etc., highlighting their association with disease severity and/or phenotype, and their potential roles in prognostic prediction and treatment selection. Some of these molecules may serve as biomarkers for aqueous humor-based companion diagnostics for the treatment of RVO in the future.

Neurovascular injury associated non-apoptotic endothelial caspase-9 and astroglial caspase-9 mediate inflammation and contrast sensitivity decline

“…EC Casp9 regulates an increase in inflammatory cytokines one day P-RVO After we found that EC Casp9 promoted a decline in vision function, we sought to evaluate the EC Casp9 downstream signaling pathway which mediates loss of vision. Inflammatory cytokines are known to be a main contributor of neovascularization, and correlate with hypoxic-ischemic injury and retinal edema [27], and are implicated in RVO pathology (summarized in the recent review [40]). Our previous work revealed that the peak of retinal edema in the EC Casp9 mouse line is two days P-RVO which coincided with a significant decrease in hyperreflective foci (HRF) (a clinical biomarker of inflammation [41][42][43]) [10].…”

Effects of Intravitreal Ranibizumab Injection on Peripheral Retinal Microcirculation and Cytokines in Branch Retinal Vein Occlusion with Macular Edema

“…In an earlier study, we showed a significant correlation between levels of MCP-1 and IL-8 in aqueous humor in BRVO [ 18 ]. In an in vivo experiment in rats, retinal vein occlusion increased the rolling and venous wall adhesion of leukocytes, markedly decreasing blood flow [ 40 ], so in BRVO with macular edema, this process may be responsible for decreasing RFV [ 41 ].…”

Anemia: A Potential Source of Bias in Clinical Trials of Angiogenesis Inhibitors: A Hypothesis

“…There is indirect evidence from human 16 and direct evidence from animal 14,17 studies that support our idea; for example, in patients with pre-existing higher EPO levels, the efficacy of anti-VEGF treatment was lower than that of patients with lower EPO levels. 18 In addition, in an animal model of musculocutaneous tissue ischemia, flaps treated with EPO and bevacizumab did not show any change in tissue necrosis when compared with animals receiving EPO only, 19 supporting a possible counteraction between EPO and anti-VEGF agents. It might be argued that the interaction between locally administered exogenous anti-VEGF and endogenous intravitreal EPO and/or VEGF levels is complex.…”