RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.

During angiogenesis, VEGF acts as an attractive cue for endothelial cells (ECs), while Sema3E mediates repulsive cues. Here, we show that the small GTPase RhoJ integrates these opposing signals in directional EC migration. In the GTP-bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1-bound RhoJ further facilitates Sema3E-induced PlexinD1-VEGFR2 association, VEGFR2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing degradation of internalized VEGFR2, prolonging downstream signal transductions via PLCγ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP-bound state, RhoJ shifts from PlexinD1 to VEGFR2, which then terminates the VEGFR2 signals. RhoJ deficiency in ECs efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTPases may act as context-dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

Flow pattern and perforating vessels in three different phases of myopic choroidal neovascularization seen by swept-source optical coherence tomography angiography.

PURPOSE: To 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). METHODS: This 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. RESULTS: Overall, 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. CONCLUSIONS: OCTA 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.

Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: an extension trial.

PURPOSE: Our 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: No 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.

Impact of photoreceptor density in a 3D simulation of panretinal laser photocoagulation.

BACKGROUND: During panretinal photocoagulation (PRP), the outer retina, especially the photoreceptors, are destroyed. During such procedures, the impact of the retinal photocoagulation, which is performed in the same photocoagulated area, may change if it is applied to different locations with different photoreceptor densities. Thus, we aimed to evaluate the influence of photoreceptor density on PRP. METHODS: We constructed a three-dimensional (3D) average distribution of photoreceptors with 3D computer-aided design (CAD) software using previously derived photoreceptor density data and calculated the number of photoreceptors destroyed by scatter PRP and full-scatter PRP (size 400-µm on the retina, spacing 1.0 spot) using a geometry-based simulation. To investigate the impact of photoreceptor density on PRP, we calculated the ratio of the number of photoreceptors destroyed to the total number of photoreceptors, termed the photoreceptor destruction index. RESULTS: In this 3D simulation, the total number of photoreceptors was 96,571,900. The total number of photoreceptors destroyed by scatter PRP and full-scatter PRP were 15,608,200 and 19,120,600, respectively, and the respective photoreceptor destruction indexes were 16.2 and 19.8%, respectively. CONCLUSIONS: Scatter PRP is expected to have 4/5 of the number of photoreceptors destroyed by full-scatter PRP.

Rho GTPases in Retinal Vascular Diseases.

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.

High-Temperature Requirement A 1 Causes Photoreceptor Cell Death in Zebrafish Disease Models.

Age-related macular degeneration (AMD) is an important cause of blindness. It is characterized by a retinal pigment epithelium (RPE) disorder that leads to death of photoreceptor cells (PRCs). AMD has a strong genetic association with high-temperature requirement A 1 (HTRA1). The relationship between HTRA1 and the AMD phenotype is unknown. In this study, we show that the expression of HTRA1 in PRCs, as well as in RPE, is increased by the disease-associated HTRA1 mutation and aging. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and quantitative PCR of apoptosis-associated caspases confirmed that PRC-specific overexpression of HTRA1 induced PRC death. Transgenic zebrafish overexpressing human HTRA1 in rod PRCs showed morphologic changes of the RPE, including PRC death and lipofuscin accumulation, features similar to those of early AMD. htra1 expression was also increased in a retinitis pigmentosa zebrafish model compared with wild type. In both fish lines, PRC death was rescued by the suppression of htra1 by the inhibitor 6-boroV. AKT-forkhead box O3 signaling downstream of HTRA1 was activated via a tumor growth factor ß signal, resulting in PRC death. These findings suggest that HTRA1 derived from PRCs is associated with early AMD via PRC death. HTRA1 is a potentially effective target for neuroprotective therapy of early AMD and other degenerative diseases of PRCs.

Effect of intravitreal injection of aflibercept or ranibizumab on chorioretinal atrophy in myopic choroidal neovascularization.

PURPOSE: To compare chorioretinal atrophy (CRA) progression in myopic choroidal neovascularization (mCNV) between intravitreal injections of ranibizumab (IVR) and aflibercept (IVA) in the eyes with mCNV. METHODS: Thirty eyes (28 patients) with treatment-naïve mCNV were included in this study. IVR or IVA was administered for up to 1 year. The best-corrected visual acuity (BCVA) was measured, and fundus photographs and fundus autofluorescence were obtained before and 1, 3, 6, and 12 months after the initial treatment. The clinical characteristics including the macular choroidal thickness in various areas and CRA progression were compared between the drugs. The clinical characteristics and macular choroidal thicknesses were compared between eyes with and without CRA progression. RESULTS: The BCVA improved significantly (p < 0.05 for all comparisons) from 0.44 to 0.26, 0.19, 0.20, and 0.17 after 1, 3, 6, and 12 months, respectively. CRA progressed in 12 (40%) eyes over 1 year. The CRA progression did not differ significantly between aflibercept and ranibizumab. The foveal choroid was significantly (p = 0.0043) thinner in aflibercept-treated eyes compared with ranibizumab-treated eyes at 1 year. Subfoveal CNV tended to cause CRA progression more frequently at 1 year, although this did not reach significance. CONCLUSIONS: IVA to treat mCNV caused more severe thinning of the foveal choroid than ranibizumab; however, no significant difference was seen in CRA progression between the drugs and the choroidal thickness should not be associated with CRA progression. The CNV location may predict CRA progression after anti-vascular endothelial growth factor therapy for mCNV.

Tachyphylaxis during treatment of exudative age-related macular degeneration with aflibercept.

PURPOSE: At 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. METHODS: Three 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. RESULTS: Twenty-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. CONCLUSIONS: Tachyphylaxis 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.

RETINAL MICROVASCULATURE AND VISUAL ACUITY AFTER INTRAVITREAL AFLIBERCEPT IN EYES WITH CENTRAL RETINAL VEIN OCCLUSION: An Optical Coherence Tomography Angiography Study.

PURPOSE: To investigate vascular perfusion and foveal avascular zone area in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) after intravitreal aflibercept therapy in central retinal vein occlusion eyes and their association with best-corrected visual acuity. METHODS: Thirty-five subjects with central retinal vein occlusion and macular edema were evaluated. After macular edema resolution following intravitreal aflibercept, subjects underwent optical coherence tomography angiography to measure SCP and DCP perfusion and the foveal avascular zone within a 3 × 3-mm area. Correlations between best-corrected visual acuity and optical coherence tomography angiography measurements were examined. RESULTS: After intravitreal aflibercept therapy, mean retinal vascular area was 3.41 ± 0.74 mm in the SCP and 3.25 ± 0.91 mm in the DCP. Foveal avascular zone area was 1.03 ± 1.04 mm in the SCP and 1.78 ± 1.73 mm in the DCP. Improved best-corrected visual acuity was significantly associated with better SCP and DCP perfusion (both P < 0.001) and with smaller SCP and DCP foveal avascular zone areas (both P < 0.001). Additionally, SCP and DCP perfusion were negatively correlated with macular edema before treatment (P < 0.05) and ischemia (determined via pretreatment fluorescein angiography, P < 0.05), and positively correlated with photoreceptor integrity (P < 0.001). CONCLUSION: Patients with better retinal perfusion and less retinal ischemia are associated with better visual outcomes after aflibercept in eyes with central retinal vein occlusion.

Retinal Blood Vessel Formation in the Macula Following Intravitreal Ranibizumab Injection for Aggressive Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Recently, anti-vascular endothelial growth factor (VEGF) drugs have been widely used for ROP to inhibit abnormal retinal angiogenesis. However, there is a concern that such drugs potentially also affect normal retinal vascular development. We report a case of blood vessel growth across the macula after anti-VEGF treatment for zone I aggressive ROP. A 25-week-old female infant was administered 0.2 mg of ranibizumab for bilateral aggressive ROP in both eyes at 33 weeks of postmenstrual age. Under normal development, retinal blood vessels do not grow into the center of the future macular region. After five weeks, however, a horizontal blood vessel sprouted from the optic disc and extended across the macula in the right eye. The blood vessel ran straight to the vascular-avascular juncture by 41 weeks of postmenstrual age during the follow-up period. While the focus has been on arresting retinal vascular development through VEGF inhibition, anti-VEGF treatment may induce vascular abnormalities in patients with severe ROP. Infants with retinal vascular abnormalities should be carefully monitored for their visual prognosis.

Morphology, Fundus Autofluorescence, and Retinal Sensitivity of Photocoagulated Lesions in Proliferative Diabetic Retinopathy.

Purpose: To evaluate the relationships among morphology, fundus autofluorescence (FAF), and retinal sensitivity of photocoagulated lesions more than 1 year after panretinal photocoagulation in patients with proliferative diabetic retinopathy and good vision. Methods: This retrospective cohort study included patients with proliferative diabetic retinopathy who had undergone panretinal photocoagulation more than 1 year ago. The photocoagulated lesions were classified according to FAF levels: group A, no FAF; group B, diffuse FAF; group C, white-dotted centers with diffuse FAF; group D, white-dotted centers without FAF; and group E, controls. The main outcome measures were FAF, retinal sensitivity, and morphology of the photocoagulated lesions. Results: The median sensitivity values and number of photocoagulated lesions in groups A (n = 37), B (n = 39), C (n = 4), D (n = 15), and E (n = 39) were 0 dB, 18.0 dB, 13.9 dB, 0.3 dB, and 21.5 dB, respectively. EZ lines were absent in 93.5%, 18.1%, 50%, 93.3%, and 0% of lesions in groups A, B, C, D, and E, respectively. The inner retinal layer was damaged in 45.2%, 3.0%, 50%, 73.3%, and 0% lesions in groups A, B, C, D, and E, respectively. Statistically significant between-group differences were observed in the retinal sensitivities of the photocoagulated lesions, presence of EZ lines, and damage to the inner retinal layer (p < 0.05). Conclusions: The photoreceptors in most photocoagulated lesions with diffuse FAF retain their morphology and function. Translational Relevance: Using fundus autofluorescence, the damage to photoreceptors after panretinal photocoagulation in patients with diabetes can be estimated in a noninvasive manner. This process can help in determining the need for additional panretinal photocoagulation.

Computer-aided detection of retinopathy of prematurity severity assessment via vessel tortuosity measurement in preterm infants' fundus images.

OBJECTIVE: To develop a computer-aided diagnostic system for retinopathy of prematurity (ROP) disease using retinal vessel morphological features. METHODS: A total of 200 fundus images from 136 preterm infants with stage 1 to 3 ROP were analysed. Two methods were developed to measure vessel tortuosity: the peak-and-valley method and the polynomial curve fitting method. Correlations between temporal artery tortuosity (TAT) and temporal vein tortuosity (TVT) with ROP severity were investigated, and vessel tortuosity relationships with vessel angles (TAA and TVA) and vessel widths (TAW and TVW). A separate dataset from Japan containing 126 images from 97 preterm patients was used for verification. RESULTS: Both methods identified similar tortuosity in images without ROP and mild ROP cases. However, the polynomial curve fit method demonstrated enhanced tortuosity detection in stages 2 and 3 ROP compared to the peak and valley method. A strong positive correlation was revealed between ROP severity and increased arterial and venous tortuosity (P < 0.0001). A significant negative correlation between TAA and TAT (r = -0.485, P < 0.0001) and TVA and TVT (r = -0.281, P < 0.0001), and a significant positive correlation between TAW and TAT (r = 0.204, P value = 0.0040) were identified. Similar results were found in the test dataset from Japan. CONCLUSIONS: ROP severity was associated with increased retinal tortuosity and retinal vessel width while displaying a decrease in retinal vascular angle. This quantitative analysis of retinal vessels provides crucial insights for advancing ROP diagnosis and understanding its progression.

Effect of polyp regression and reduction on treatment efficacy in polypoidal choroidal vasculopathy treated with aflibercept.

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.

Comparison of Loading Dose between Aflibercept and Faricimab for Neovascular Age-Related Macular Degeneration.

BACKGROUND: Recently, faricimab was approved as the new drug for neovascular age-related macular degeneration (nAMD). We lack the knowledge to choose between the existing drug and this new drug to use for treatment-naïve nAMD cases. In this study, we compared the functional and morphologic effects in loading dose between patients with treatment-naïve nAMD treated with either intravitreal aflibercept (IVA) or intravitreal faricimab (IVF) injection in a clinical setting. METHOD: This retrospective study included 30 eyes of 28 patients who started treatment with IVA between June and September 2022 and 30 eyes of 29 patients who were administered IVF between October 2022 and March 2023. All patients received three monthly IVA or IVF. The best corrected visual acuity (BCVA), central retinal thickness (CRT), and the proportion of eyes with residual exudative change at baseline and 1,2, and 3 months after initial treatment were compared between the groups. RESULTS: The mean BCVA significantly improved from pre-treatment after the loading dose in the IVA group (0.46 ± 0.46-0.36 ± 0.37, p = 0.0047) but not in the IVF group (0.46 ± 0.41-0.44 ± 0.45, p = 0.60). The mean CRT significantly improved in both groups. The proportion of eyes with residual exudative change was greater in the IVF group than in the IVA group 2 months after the first treatment (p = 0.026). The analysis of cases that achieved complete resolution of exudative changes after the loading dose showed that the IVA group had a significant improvement in the BCVA, whereas the IVF group did not (p = 0.0047 and 0.20, respectively). CONCLUSIONS: Although both IVA and IVF significantly improved CRT, the BCVA improved significantly in the IVA group but not in the IVF group.

Continuous oxygen saturation and risk of retinopathy of prematurity in a Japanese cohort.

BACKGROUND/AIMS: We assessed the associations between retinopathy of prematurity (ROP) and continuous measurements of oxygen saturation (SpO2), and developed a risk prediction model for severe ROP using birth data and SpO2 data. METHODS: This retrospective study included infants who were born before 30 weeks of gestation between August 2009 and January 2019 and who were screened for ROP at a single hospital in Japan. We extracted data on birth weight (BW), birth length, gestational age (GA) and minute-by-minute SpO2 during the first 20 days from the medical records. We defined four SpO2 variables using sequential measurements. Multivariate logistic regression was used to develop a model that combined birth data and SpO2 data to predict treatment-requiring ROP (TR-ROP). The model's performance was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Among 350 infants, 83 (23.7%) required ROP treatment. The SpO2 variables in infants with TR-ROP differed significantly from those with non-TR-ROP. The average SpO2 and high SpO2 showed strong associations with GA (r=0.73 and r=0.70, respectively). The model incorporating birth data and the four SpO2 variables demonstrated good discriminative ability (AUC=0.83), but it did not outperform the model incorporating BW and GA (AUC=0.82). CONCLUSION: Data obtained by continuous SpO2 monitoring demonstrated valuable associations with severe ROP, as well as with GA. Differences in the distribution of average SpO2 and high SpO2 between infants with TR-ROP and non-TR-ROP could be used to establish efficient cut-off values for risk determination.

An Association between HTRA1 and TGF-ß2 in the Vitreous Humor of Patients with Chorioretinal Vascular Diseases.

Background: The aim of this paper was to investigate the protein concentrations of high-temperature requirement A 1 (HTRA1) and transforming growth factor-ß (TGF-ß) in the vitreous humor of patients with chorioretinal vascular diseases. Methods: This study measured protein concentrations of HTRA1, TGF-ß1-3, and vascular endothelial growth factor A (hereinafter called VEGF) in the vitreous humor from seven eyes of patients with chorioretinal vascular diseases (age-related macular degeneration, diabetic macular edema, and retinal vein occlusion) and six control eyes (idiopathic epiretinal membrane and macular hole). We analyzed the mutual relationship among the protein levels. Results: The protein levels of HTRA1 and VEGF were significantly increased in the chorioretinal vascular disease group compared with the control group (1.57 ± 0.79 ×10-9 mol/mL vs. 0.68 ± 0.79 ×10-9 mol/mL, p = 0.039; 3447.00 ± 3423.47 pg/mL vs. 35.33 ± 79.01 pg/mL, p = 0.046, respectively). TGF-ß2 levels were not significantly different between groups (2222.71 ± 1151.25 pg/mL for the chorioretinal vascular disease group vs. 1918.83 ± 744.01 pg/mL for the control group, p = 0.62). The concentration of HTRA1 was strongly associated with TGF-ß2 levels in the vitreous humor, independent of VEGF (r = 0.80, p = 0.0010). Conclusions: We revealed that vitreous HTRA1 was increased in patients with chorioretinal vascular diseases and strongly correlated with TGF-ß2.

[RhoJ signaling pathway in retinal angiogenesis: promising targets for novel anti-angiogenic therapy].

In quiescent retinal vessels, adjacent endothelial cells (ECs) form a tightly sealed junction, leading to maintenance of vascular integrity. By contrast, during pathological angiogenesis in diabetic retinopathy and age-related macular degeneration, vascular endothelial growth factor (VEGF) activates intracellular signaling pathways in ECs, resulting in the dissociation of cell-cell adhesions and induction of EC migration. To inhibit undesirable angiogenesis, it would be clinically beneficial to manipulate intracellular signals that control migratory behavior of ECs. Here we show that the small GTPase RhoJ is expressed predominantly in angiogenic ECs, and regulates cell motility through cytoskeletal rearrangement. We also found that Arhgef15, an EC-specific guanine nucleotide exchange factor, inactivates RhoJ downstream of VEGF signals, thereby promoting retinal vascular growth. These signaling molecules can be potential drug targets for novel antiangiogenic therapy.

Three cases of macular retinal detachment exacerbated during follow-up with myopic foveoschisis around myopic choroidal neovascularization.

Purpose: Myopic choroidal neovascularization (CNV) and myopic traction maculopathy are major complications of pathologic myopia, and myopic foveoschisis (MF) is one of several symptoms that can be included under the general term "myopic traction maculopathy"; however, only a few cases will have MF around the myopic CNV. We report three cases with MF around myopic CNV that followed different clinical courses observed using swept-source optical coherence tomography. Observations: Case 1 was a 69-year-old woman with an axial length of 29.71 mm, myopic CNV, and MF in the left eye. One month after intravitreal injection of ranibizumab (IVR), a macular retinal detachment (RD) expanded. Vitrectomy and gas tamponade were performed during month 2; the macular RD and MF resolved gradually thereafter. Case 2 was a 54-year-old man with an axial length of 30.59 mm, myopic CNV, and MF in the right eye; after IVR, a macular RD developed and gradually expanded until month 4; the RD and MF resolved spontaneously and resolved during month 8. Case 3 was a 66-year-old woman with an axial length of 28.63 mm, myopic CNV, and MF in the left eye. A macular RD expanded 1 month after a previous vitrectomy for MF; after intravitreal injection of aflibercept, the macular RD and MF resolved gradually in month 12. In all cases, the CNV was accompanied by subretinal fluid, and two of the three cases had outer lamellar holes. Conclusion and Importance: The MF around the myopic CNV may lead to exacerbated MF and RD during follow-up, and the subretinal fluid caused by the CNV might facilitate MF progression. Since this condition is rare, further investigation of this entity is needed to determine appropriate management.