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The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell–cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases.

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities-including hyperpermeability, hypoperfusion, and neoangiogenesis-that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

We investigated changes in retinal vascular area and the foveal avascular zone (FAZ) after intravitreal aflibercept in diabetic macular edema (DME) and the association of these changes with visual outcomes. The retinal vascular area in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) and the FAZ area were measured using optical coherence tomography angiography (OCTA) in 23 eyes of 23 patients with DME, before and after intravitreal aflibercept. Overall, there was no significant change in retinal vascular area or FAZ. Better BCVA after treatment was significantly associated with larger retinal vascular area in the SCP and the DCP, both at baseline (R 2  = 0.512, P < 0.001 and R 2  = 0.361, P = 0.002, respectively) and after intravitreal aflibercept (R 2  = 0.717, P < 0.001 and R 2  = 0.618, P < 0.001, respectively). MAs were observed in the DCP in 20 eyes (87%), but only detected in four eyes (17%) in the SCP before treatment. The number of eyes with MAs in the DCP significantly decreased to 13 (57%) after treatment (P = 0.049). The persistence of DME was associated with persistent MAs (P = 0.019) and less visual gain (P = 0.031) following treatment. Thus, preserving retinal perfusion and the resolution of MAs are associated with better vision and resolution of the DME after intravitreal aflibercept.

PurposeAt present, the standard treatment of neovascular age-related macular degeneration (AMD) is the repeated administration of antivascular endothelial growth factor (VEGF) agents. However, we often encounter patients who develop tachyphylaxis for anti-VEGF agents. In this study, we investigated the characteristics of patients who developed tachyphylaxis on repeated intravitreal aflibercept (IVA) injections for neovascular AMD and the frequency of tachyphylaxis.MethodsThree hundred thirteen eyes (313 patients) with treatment-naïve AMD who achieved resolution soon after starting IVA and were followed up for ≥ 12 months were enrolled in this retrospective, interventional, consecutive case series. The eyes were investigated for tachyphylaxis to aflibercept. Tachyphylaxis was defined as absence of any improvement (more than 100 μm) in or worsening of CRT within 1 month after more than two repeated monthly IVA injections when the exudative change remained.ResultsTwenty-eight (8.9%) of the 313 eyes developed tachyphylaxis (occult with no classic, n = 14; polypoidal choroidal vasculopathy, n = 14) at an annual rate of about 3%. The mean number of IVA injections was 10.5 ± 7.8, and the mean interval until tachyphylaxis was 20.9 ± 14.0 months. There was a significant difference in the AMD subtypes between the group with tachyphylaxis and the group without it (p = 0.0029). Occult with no classic type and polypoidal choroidal vasculopathy were the only AMD subtypes in the eyes with tachyphylaxis. In the analysis of the eyes that had occult with no classic or polypoidal choroidal vasculopathy, only intraretinal edema was significantly less common (p = 0.042). A combination of photodynamic therapy and aflibercept was effective in 13 (87%) of 15 eyes with tachyphylaxis, and switching to intravitreal ranibizumab was effective in 5 (56%) of 9 eyes.ConclusionsTachyphylaxis occurs after repeated IVA injections in a minority of patients with AMD for a long term and is more likely to occur in eyes with lesions beneath the retinal pigment epithelium and no intraretinal edema. Treatment of AMD should be performed keeping this fact in mind, while considering the consecutive treatment.

Intravitreal injection of aflibercept (IVA) has successfully treated polypoidal choroidal vasculopathy (PCV), and polyp morphology is an important indicator of treatment efficacy. However, many studies have not reported the presence or absence of polyp regression and treatment outcomes, and few studies have reported polyp reduction and treatment outcomes in cases with residual polyps. We retrospectively measured the polyp area on indocyanine green angiography images before and after the IVA loading phase and investigated the regression and reduction of polyps and treatment outcomes of 81 eyes with PCV treated with IVA. We investigated the relationship between the presence or absence of complete regression of polyps and the percentage change in the polyp area and treatment outcomes. Eyes with complete polyp regression had significantly better visual acuity improvements compared with baseline at 12 months ( P  = 0.0108), fewer treatments ( P  = 0.0024), fewer recurrences during 12-months follow-up ( P  = 0.0010), and more “dry maculas” at 3 months ( P  = 0.0048) than eyes in which polyp regression did not occur. A significant correlation was seen only between the percentage of polyp regression and visual acuity at 3 months ( P  = 0.0395). Regarding IVA therapy for PCV, the presence or absence of complete polyp regression at the end of the loading phase affected the treatment outcome, whereas the degree of polyp reduction in cases of residual polyps had no effect.

Cells of the retina, photoreceptors especially, are highly metabolically active with substantial energy requirements. Accordingly, the effective delivery of oxygen and nutrients to the retina via the retinal vasculature is key to tissue function. Indeed, a disturbed retinal blood supply, especially if prolonged, can result in a loss of vision. Vascular endothelial cells, which form the inner lining of blood vessels, are pivotal in ensuring a healthy blood circulation in many tissues, including the light-sensitive retina at the back of the eye. However, the mechanism by which vascular endothelial cells maintain a functional retina (and aid the healing of a damaged one) is not understood. Here, through single-cell RNA sequencing, colony-forming assays and lineage tracing analysis, we provide data that point to a new regulatory system by which vascular endothelial cells are supplied to the retina by a reservoir of stem/progenitor cells in the optic nerve. This study finds stem-like endothelial cells in the optic nerve that supply and repair retinal blood vessels after injury, revealing a hierarchical repair system that may enable new treatments for blinding vascular eye diseases.

PurposeTo compare the choroidal neovascularization (CNV) flow patterns and the relationship between perforating vessels (PVs) and CNV in the three different stages of networks in myopic CNV (mCNV) using swept-source optical coherence tomography angiography (SS-OCTA).MethodsThis retrospective study included 28 eyes with mCNV that was divided into three phases (active, scar, and atrophic) and observed by SS-OCTA. SS-OCTA findings, with special focus on the relationship between the PVs and CNV, were compared among the three phases.ResultsOverall, the CNV signal was detected in 31 of the 34 areas of CNV (91%); in the active, scar, and atrophic phases, respectively, CNV signals were detected in eight of eight areas of CNV (100%), 10 of 11 areas of CNV (91%), and 13 of 15 areas of CNV (86%). Two signal patterns were observed in each phase, i.e., dense and loop; in the atrophic phase, seven eyes were unclassifiable. The ratio between the dense and loop patterns did not differ significantly among the phases. In 30 of 34 areas of CNV for which clear images were obtained, the PVs and CNV were connected directly or indirectly in 19 area of CNV, and in five areas of CNV, trunk-like vessels were connected to the PVs within the CNV. The numbers of foveal or parafoveal CNVs accompanied by PVs were significantly (p=0.0048) greater than those of the extrafoveal CNV.ConclusionsOCTA provides detailed observation of mCNV and the relationship between CNV and PVs. Although the CNV signal pattern does not differ depending on the degree of atrophy, there are cases in which only the trunk-like vessels connect to the PVs within the CNV in the atrophic phase without CNV flow signal.

PurposeOur previous 1-year pilot study evaluated the efficacy of intravitreally injected activated protein C (APC) in 10 eyes with ischemic central retinal vein occlusion (CRVO). The reperfusion of the areas of retinal nonperfusion (RNP) exceeded 50% of the baseline in five (50%) eyes 1 year after the APC injection. The current study evaluated the long-term efficacy and safety of intravitreal APC.MethodsThe 10 eyes in the pilot study were included in this study. Other treatments were administered at the physicians’ discretion after the pilot study. We evaluated visual acuity (VA), central retinal thickness (CRT) and perfusion status, and adverse events and severity over the long term.ResultsThe median follow-up was 60 months (range, 48–68 months). Compared with baseline, the post-treatment VA improved significantly (P < 0.001) from 1.39 to 1.06 logarithm of the minimum angle of resolution. The CRT improved significantly (P < 0.001) from 1090 to 195 μm at the last visit. The RNP areas decreased from an average 29.7 disc areas (DAs) at baseline to an average 16.5 DAs at the last examination (mean, 40 ± 6.5 months after the first APC treatment). No adverse events were related to intravitreal APC.ConclusionNo complications were associated with intravitreal APC, the clinical course improved, and improved RNP was maintained for the long term, suggesting that intravitreal APC may be an alternative treatment for CRVO.

Although choriocapillaris flow deficit (CFD) around choroidal neovascularization (CNV) is less associated with CNV activity in myopic eyes, no reports are investigating its size as an indicator of CNV activity. We investigated the relationship between CFD and high myopia-related CNV. In this retrospective, observational study, patients underwent optical coherence tomography angiography (OCTA) with split-spectrum amplitude-decorrelation angiography for diagnosing pathological myopic CNV (mCNV); CFD features around CNV margins were evaluated. Of the 33 eyes (30 patients), 11 (33.3%) had active mCNV, and 22 (66.7%) had inactive CNV. Six eyes (18.2%) were treatment-naïve, while the remainder previously underwent anti-vascular endothelial growth factor therapy. On OCTA, blood flow signals were detected in CNV in the outer retinal layer in 28 (84.8%) eyes, including all active cases (11 cases) and 17 (77.3%) of 22 inactive cases. CNV flow signal size correlated significantly with activity (P < 0.001). CFD around CNV was observed in 24 eyes (72.7%), including all active cases (11 cases) and 13 (59.1%) of 22 inactive cases. CFD size correlated significantly with CNV activity (P < 0.001). The size of both the CFD area around CNV and CNV flow signal area are useful indicators of CNV activity in eyes with mCNV, which may help determine treatment timing.