RVO is the second common retinal vascular disease that impairs vision after diabetic retinopathy . Although there are many treatment measures, such as laser photocoagulation, pharmacological agents, and surgical options , intravitreal injection of anti-VEGF improved visual acuity and reduce the macular edema, which is becoming the first-line therapy for the treatment of RVO-ME . The research showed that VEGF not only activates vascular endothelial growth factor receptor 2 (VEGFR2), leading to the reduction of tight junctions and the destruction of BRB, but also stimulates endothelial cells to production of a vasodilator, nitric oxide (NO), and increase intercellular cell adhesion molecule-1 (ICAM-1) expression [13, 14]. Besides VEGF is also an important stimulator for the activation of inflammatory cells, such as microglia and mononuclear phagocytes. Through binding VEGF, anti-VEGF therapy becomes the first-line therapy in the treatment of RVO-ME .
In this study, the improvement of visual acuity and decrease of macular edema were observed after anti-VEGF treatments, demonstrating that anti-VEGF therapy is very effective for patients with RVO-ME. Besides, BCVA and CMT, other parameters related to RVO were also analyzed, including vessel density, FAZ, HRF, and SRF, etc. The vessel density of SCP and DCP can be well identified and calculated with OCTA auto-segmentation software. Winegarner A. et.al  reported that the relationship between the decreased vessel density and visual impairment in RVO. The FAZ area was suggested as a biomarker to for local retinal ischemia within macular region [17, 18], and previous study showed that progressive enlargement of FAZ after anti-VEGF therapy in cystoid ME secondary to diabetic retinopathy or RVO , indicating the macular ischemia. However, in our study, no significant changes for vessel density and FAZ area before and after anti-VEGF treatments, which is consistent with the previous study .
The mechanism of NPA formation remains unclear. Some researchers speculated the causative may compression of capillaries by swollen retinal tissues, arterial insufficiency based on back pressure by the obstructed veins, or capillary occlusion due to leukocyte accumulation at the endothelium. NPA usually considered similar to ischemia, and the size of NPA can distinguish the ischemic and nonischemic types in RVO . Here, the decrease of NPA was observed after anti-VEGF treatment. The present study indicated that early and promptly treatment will benefit the patients more due to alleviate the ischemic condition of macula. It is suggested that anti-VEGF improved blood flow and oxygen supply, reduced the expression of VEGF and ICAM-A, and suppressed the accumulation of leukocyte, leading to reduction of NPA. The detailed mechanisms for NPA decrease after anti-VEGF treatment remains further exploration.
Chen et.al  reported that HRF associated with acquired vitelliform lesions were of RPE origin from a donor eye. HRF might as a biomarker associated with the activity and severity of choroideremia. It related to macrophages/microglial activation or progressive PRE degeneration . HRF position was positively associated with final visual outcome, and varied in different diseases depending on various pathologic mechanisms . With aid of OCTA, we found HRF distributed in all the retina layers in patients with RVO-ME, and the number of HRF were decreased significantly after anti-VEGF treatment. At the same time, the restoration of microstructure of the outer retina was observed, including the myoid zone (MZ), ellipsoid zone (EZ), the outer segments of the photoreceptors (OS) and interdigitation zone (IZ) / RPE after anti-VEGF therapy. It also showed that SRF absorption might contribute to the repair of the microstructure and function of retina. Kang, J. W. et.al  reported that the more rupture of the external limiting membrane (ELM) structure, the less intact, and the greater the amount of HRF, no matter CRVO or BRVO.
The CMT, defined as the mean thickness of the central 1 mm circle centered on the fovea, is the most used parameter to evaluate ME . The significant reduction of CMT in our study implied that ME or SRF were absorbed rapidly after anti-VEGF. RPE functions as to maintain the permeability of transepithelial gradient generated by ion pumps and ion channels, and to avoid paracellular flow. The fluid movement between cells follows the principle of osmotic gradient, flowing from the retina toward to the choroid . In RVO-ME, the function of RPE is impaired, resulting in restricted drainage function, causing SRF. The decrease of SRF after anti-VEGF treatment indicated the improvement of RPE drainage function by anti-VEGF, although the detailed mechanisms need further study.
Pervious study showed that the level of inflammatory cytokines, including VEGF, was elevated in either aqueous or vitreous samples, which was associated with the severity of ME [4, 26]. VEGF has also been reported to increase vascular permeability by increasing the phosphorylation of tight junction proteins. As mentioned before, the mechanism for RVO-ME is complex , with other factors involved, such as interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and pigment epithelial-derived factor (PEDF) [3, 7]. Thus, it would be more accurate if personized treatment for RVO-ME is initiated. More in-depth research and more precise combination treatments are needed in the future.
In summary, anti-VEGF is effective for the treatment of RVO-ME, in terms of visual acuity improve and reduction of macular edema. The absorption of SRF indicated the restoration of RPE drainage function by anti-VEGF treatment; while the decrease of HRF and NPA might indicate anti-inflammatory effect by anti-VEGF treatment to deactivate the inflammatory cells (Fig. 4).