Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy.

Activation of hypoxia-inducible factor 1α (HIF1α) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1α degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy.

Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis.

Normal angiogenesis is essential for retinal development and maintenance of visual function in the eye, and its abnormality can cause retinopathy and other eye diseases. Prostaglandin D2 is an anti-angiogenic lipid mediator produced by lipocalin-type PGD synthase (L-PGDS) or hematopoietic PGD synthase (H-PGDS). However, the exact role of these PGD synthases remains unclear. Therefore, we compared the roles of these synthases in murine retinal angiogenesis under physiological and pathological conditions. On postnatal day (P) 8, the WT murine retina was covered with an elongated vessel. L-PGDS deficiency, but not H-PGDS, reduced the physiological vessel elongation with sprouts increase. L-PGDS expression was observed in endothelial cells and neural cells. In vitro, L-PGDS inhibition increased the hypoxia-induced vascular endothelial growth factor expression in isolated endothelial cells, inhibited by a prostaglandin D2 metabolite, 15-deoxy-Δ12,14 -PGJ2 (15d-PGJ2) treatment. Pericyte depletion, using antiplatelet-derived growth factor receptor-ß antibody, caused retinal hemorrhage with vessel elongation impairment and macrophage infiltration in the WT P8 retina. H-PGDS deficiency promoted hemorrhage but inhibited the impairment of vessel elongation, while L-PGDS did not. In the pericyte-depleted WT retina, H-PGDS was expressed in the infiltrated macrophages. Deficiency of the D prostanoid receptor also inhibited the vessel elongation impairment. These results suggest the endogenous role of L-PGDS signaling in physiological angiogenesis and that of H-PGDS/D prostanoid 1 signaling in pathological angiogenesis.

RHOJ controls EMT-associated resistance to chemotherapy.

The resistance of cancer cells to therapy is responsible for the death of most patients with cancer1. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells2,3. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ-a small GTPase that is preferentially expressed in EMT cancer cells-controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.

Effect of triamcinolone acetonide on retinal inflammation and angiogenesis induced by pericyte depletion in mouse.

Triamcinolone acetonide (TA) has been shown to improve morphological and functional outcome in diabetic macular edema (DME) patients. However, the functional mechanism of TA has not been elucidated yet. In this study we investigated the detailed functional mechanism of TA using culture cells and retinopathy mouse models in which retinal inflammation and abnormal angiogenesis were induced by pericyte depletion. TA significantly prevented retinal hemorrhage, edema and partially improved abnormal angiogenesis. TA decreased retinal vascular endothelial growth factor (VEGF) concentration, presumably by preventing recruitment of macrophages into retina and TA also inhibited expression of inflammatory cytokines in retina. TA inhibited proliferation/migration of vascular endothelial cells and vessel sprouting. No direct inhibition of VEGF receptor 2 (VEGFR2) autophosphorylation was observed by TA. These results suggested that TA improved inflammatory retinal events which were induced in pericyte-deleted mice by mainly decreasing macrophage-derived VEGF and expression of inflammatory cytokines followed by attenuation of vascular permeability and proliferation/migration of endothelial cells. Furthermore, in these processes, translocation of glucocorticoid receptor (GR) was partially involved.

Quantitative modeling of regular retinal microglia distribution.

Microglia are resident immune cells in the central nervous system, showing a regular distribution. Advancing microscopy and image processing techniques have contributed to elucidating microglia's morphology, dynamics, and distribution. However, the mechanism underlying the regular distribution of microglia remains to be elucidated. First, we quantitatively confirmed the regularity of the distribution pattern of microglial soma in the retina. Second, we formulated a mathematical model that includes factors that may influence regular distribution. Next, we experimentally quantified the model parameters (cell movement, process formation, and ATP dynamics). The resulting model simulation from the measured parameters showed that direct cell-cell contact is most important in generating regular cell spacing. Finally, we tried to specify the molecular pathway responsible for the repulsion between neighboring microglia.

VEGFR1 signaling in retinal angiogenesis and microinflammation.

Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.

A new perfusion culture method with a self-organized capillary network.

A lack of perfusion has been one of the most significant obstacles for three-dimensional culture systems of organoids and embryonic tissues. Here, we developed a simple and reliable method to implement a perfusable capillary network in vitro. The method employed the self-organization of endothelial cells to generate a capillary network and a static pressure difference for culture medium circulation, which can be easily introduced to standard biological laboratories and enables long-term cultivation of vascular structures. Using this culture system, we perfused the lumen of the self-organized capillary network and observed a flow-induced vascular remodeling process, cell shape changes, and collective cell migration. We also observed an increase in cell proliferation around the self-organized vasculature induced by flow, indicating functional perfusion of the culture medium. We also reconstructed extravasation of tumor and inflammatory cells, and circulation inside spheroids including endothelial cells and human lung fibroblasts. In conclusion, this system is a promising tool to elucidate the mechanisms of various biological processes related to vascular flow.

Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation.

OBJECTIVE: The calcineurin-NFAT (nuclear factor for activated T cells)-DSCR (Down syndrome critical region)-1 pathway plays a crucial role as the downstream effector of VEGF (vascular endothelial growth factor)-mediated tumor angiogenesis in endothelial cells. A role for DSCR-1 in different organ microenvironment such as the cornea and its role in ocular diseases is not well understood. Corneal changes can be indicators of various disease states and are easily detected through ocular examinations. Approach and Results: The presentation of a corneal arcus or a corneal opacity due to lipid deposition in the cornea often indicates hyperlipidemia and in most cases, hypercholesterolemia. Although the loss of Apo (apolipoprotein) E has been well characterized and is known to lead to elevated serum cholesterol levels, there are few corneal changes observed in ApoE-/- mice. In this study, we show that the combined loss of ApoE and DSCR-1 leads to a dramatic increase in serum cholesterol levels and severe corneal opacity with complete penetrance. The cornea is normally maintained in an avascular state; however, loss of Dscr-1 is sufficient to induce hyper-inflammatory and -oxidative condition, increased corneal neovascularization, and lymphangiogenesis. Furthermore, immunohistological analysis and genome-wide screening revealed that loss of Dscr-1 in mice triggers increased immune cell infiltration and upregulation of SDF (stromal derived factor)-1 and its receptor, CXCR4 (C-X-C motif chemokine ligand receptor-4), potentiating this signaling axis in the cornea, thereby contributing to pathological corneal angiogenesis and opacity. CONCLUSIONS: This study is the first demonstration of the critical role for the endogenous inhibitor of calcineurin, DSCR-1, and pathological corneal angiogenesis in hypercholesterolemia induced corneal opacity.

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.

Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis.

RATIONALE: Central nervous system has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for vascular barrier in central nervous system, suppressed transcytosis in endothelial cells is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly causes diseases associated with edema remain elusive. Dll4 signaling is important for various vascular contexts, but its role in the maintenance of vascular barrier in central nervous system remains unknown. OBJECTIVE: To find a TJ-independent regulatory mechanism selective for transcytosis and identify its dysregulation as a cause of pathological leakage. METHODS AND RESULTS: We studied transcytosis in the adult mouse retina with low vascular permeability and employed a hypertension-induced retinal edema model for its pathological implication. Both antibody-based and genetic inactivation of Dll4 or Notch1 induce hyperpermeability by increasing transcytosis without junctional destabilization in arterial endothelial cells, leading to nonhemorrhagic leakage predominantly in the superficial retinal layer. Endothelial Sox17 deletion represses Dll4 in retinal arteries, phenocopying Dll4 blocking-driven vascular leakage. Ang II (angiotensin II)-induced hypertension represses arterial Sox17 and Dll4, followed by transcytosis-driven retinal edema, which is rescued by a gain of Notch activity. Transcriptomic profiling of retinal endothelial cells suggests that Dll4 blocking activates SREBP1 (sterol regulatory element-binding protein 1)-mediated lipogenic transcription and enriches gene sets favorable for caveolae formation. Profiling also predicts the activation of VEGF (vascular endothelial growth factor) signaling by Dll4 blockade. Inhibition of SREBP1 or VEGF-VEGFR2 (VEGF receptor 2) signaling attenuates both Dll4 blockade-driven and hypertension-induced retinal leakage. CONCLUSIONS: In the retina, Sox17-Dll4-SREBP1 signaling axis controls transcytosis independently of TJ in superficial arteries among heterogeneous regulations for the whole vessels. Uncontrolled transcytosis via dysregulated Dll4 underlies pathological leakage in hypertensive retina and could be a therapeutic target for treating hypertension-associated retinal edema.

Ursodeoxycholic Acid Attenuates the Retinal Vascular Abnormalities in Anti-PDGFR-ß Antibody-Induced Pericyte Depletion Mouse Models.

As a clinical manifestations of diabetic retinopathy (DR), pericytes (PCs) loss from the capillary walls is thought to be an initial pathological change responsible for the breakdown of the blood-retinal barrier (BRB). This study was performed to investigate the effects of ursodeoxycholic acid (UDCA) in PC depletion mice by injection of an antibody against platelet-derived growth factor reception-ß (PDGFR-ß clone APB5). To assess the integrity of the retinal vessels, their density, diameters, vessel branching points, and number of acellular capillaries were evaluated. While all types of retinal vessels became enlarged in APB5-induced mice, treatment with UDCA rescued the vasculature; the vessel density, diameter of the veins and capillaries, and vessel branching points were significantly lower in mice treated with UDCA. Although APB5-induced mice displayed progressive exacerbation of retinal edema, whole retinal thickness upon treatment with UDCA was significantly decreased. Additionally, UDCA reduced the expression of F4/80+ macrophages in the APB5-induced retina according to immunofluorescent labeling. UDCA also reduced the increased expression of angiogenic factors and inflammatory mediators (vascular endothelial growth factor, intercellular adhesion molecule-1, and monocyte chemotactic protein-1). These findings suggest that UDCA can be used to prevent the progression of and treat DR.

Structural and Functional Analyses of Retinal Ischemia in Eyes with Retinal Vein Occlusion: Relationship with Macular Edema or Microaneurysm Formation.

PURPOSE: To study the structural and functional changes of retinal ischemia and investigate their association with macular edema (ME) or microaneurysm (MA) formation in eyes with retinal vein occlusion (RVO). METHODS: Sixty eyes of 30 patients (27 eyes with branch [b]RVO, 3 with central RVO, and 30 fellow eyes) were retrospectively reviewed. Optical coherence tomography (OCT), OCT angiography (OCTA), and microperimetry were performed simultaneously to measure retinal thickness and sensitivity. The presence of ME or MA was also assessed using OCT and fluorescein angiography. RESULTS: The mean retinal sensitivity in the nonperfused areas (NPAs) deteriorated, and this was significantly (r = -0.379, p = 0.0391*) and inversely correlated with duration from disease onset. ME and MA were unlikely to be observed around the area where the retinal sensitivity decreased. In the NPAs, the mean retinal thickness of the superficial capillary plexus (SCP) (p < 0.0001), deep capillary plexus (DCP) (p = 0.0323), and outer retina (p = 0.0008) were significantly thinner than those in the fellow eyes, respectively. Multivariate regression analysis revealed that the thicknesses of the DCP (ß: 0.3107, p = 0.0007) and outer retina (ß: 0.3482, p = 0.0001) were the independent correlative factors of the retinal sensitivity, but that SCP thickness was not. CONCLUSION: Deep retinal thinning in NPAs was correlated significantly with a decreased retinal sensitivity, which might be a negative predictor of ME and MA in eyes with RVO.

Inhibition of stromal cell-derived factor-1α/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas.

In diabetic retinopathy (DR), pericyte dropout from capillary walls is believed to cause the breakdown of the blood-retina barrier (BRB), which subsequently leads to vision-threatening retinal edema. While various proinflammatory cytokines and chemokines are upregulated in eyes with DR, their distinct contributions to disease progression remain elusive. Here, we evaluated roles of stromal cell-derived factor-1α (SDF-1α) and its receptor CXCR4 in the BRB breakdown initiated by pericyte deficiency. After inhibition of pericyte recruitment to developing retinal vessels in neonatal mice, endothelial cells (ECs) upregulated the expression of SDF-1α. Administration of CXCR4 antagonists, or EC-specific disruption of the CXCR4 gene, similarly restored the BRB integrity, even in the absence of pericyte coverage. Furthermore, CXCR4 inhibition significantly decreased both the expression levels of proinflammatory genes (P < 0.05) and the infiltration of macrophages (P < 0.05) into pericyte-deficient retinas. Taken together, EC-derived SDF-1α induced by pericyte deficiency exacerbated inflammation through CXCR4 in an autocrine or paracrine manner and thereby induced macrophage infiltration and BRB breakdown. These findings suggest that the SDF-1α/CXCR4 signaling pathway may be a potential therapeutic target in DR.

Sympathetic ophthalmia in fellow eye after vitrectomy for massive subretinal hemorrhage secondary to polypoidal choroidal vasculopathy.

We experienced a case of sympathetic ophthalmia in a fellow eye after vitrectomy for subretinal hemorrhage related to polypoidal choroidal vasculopathy. A 60-year-old male consulted us for polypoidal choroidal vasculopathy with subretinal hemorrhage in his left eye. The recurrence of massive subretinal hemorrhage refractory to repeated pars plana vitrectomies leads to phthisis bulbi. Two months later, multiple serous retinal detachments were observed in his right eye. Positive human leukocyte antigen-DR4 and the uveitis were helpful in distinguishing between sympathetic ophthalmia and age-related macular degeneration. High-dose pulse intravenous steroid contributed to recovery of visual acuity after resolution of serous retinal detachment.

Flattening of retinal pigment epithelial detachments after pneumatic displacement of submacular hemorrhages secondary to age-related macular degeneration.

PURPOSE: Pneumatic displacement of submacular hemorrhages (SMHs) with intravitreal injection of sulfur hexafluoride (SF6) gas with or without tissue plasminogen activator (tPA) and prone posturing is an effective minimally invasive treatment. We observed some cases in which simultaneous flattening of hemorrhagic pigment epithelial detachments (PEDs) occurred after prone posturing. This study evaluated the impact of pneumatic displacement using tPA to treat PEDs and visual outcomes in eyes with SMHs secondary to neovascular age-related macular degeneration (AMD). METHODS: This retrospective analysis reviewed the medical records of 32 patients (33 eyes) who underwent pneumatic displacement for AMD-associated SMHs. The SMHs were related to polypoidal choroidal vasculopathy (PCV) in 24 eyes and typical AMD in nine eyes and treated with intravitreal injection of SF6 gas with tPA. We assessed the postoperative best-corrected visual acuities (BCVAs), prevalence and flattening rates of the PEDs, and the number of additional treatments. RESULTS: The mean follow-up period was 35.4 ± 19.8 months. The BCVAs improved significantly in eyes with PCV compared with eyes with typical AMD. Thirty-one (93.9%) of 33 eyes had an accompanying PED. The PEDs flattened in 14 (58.3%) of 24 eyes with PCV but in only one (14.3%) of seven eyes with typical AMD (p = 0.04). A mean of one additional treatment was administered during the first year in 15 eyes with flattened PEDs, which was significantly (p < 0.05) fewer than the 3.6 additional treatments in 16 eyes with persistent PEDs. CONCLUSIONS: PEDs often accompany SMHs secondary to neovascular AMD. Pneumatic displacement of the SMHs using tPA unexpectedly flattened the PEDs, especially in eyes with PCV, and was associated with fewer additional treatments.

A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice.

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.

Pharmacologic management of diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age populations, primarily attributable to retinal vascular hyperpermeability, hypoperfusion, and neoangiogenesis. In the past decade, laser photocoagulation and surgical interventions to treat DR have been replaced by topical administrations of anti-vascular endothelial growth factor drugs and corticosteroids. Although these drugs have revolutionized clinical management of DR, their limited efficacy and adverse effects have raised an increasing demand for new drug development. Meanwhile, mouse retinas have been prevalently employed as an experimental model system for angiogenic research, which has greatly contributed to the understanding of general principles in vascular biology. Therefore, clinical ophthalmology and basic research have complimentarily accumulated invaluable information for DR drug discovery. This review highlights the current pharmacologic management of DR, the utility of experimental mouse retinal models, and the perspectives on new drugs targeting the angioepoitin-Tie2 signals.

Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown.

In the central nervous system, endothelial cells (ECs) and pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural homeostasis. However, in diabetic retinopathy (DR), the loss of PCs from vessel walls is assumed to cause breakdown of the blood-retina barrier (BRB) and subsequent vision-threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by using an anti-PDGFRß antibody, we show that transient inhibition of the PC recruitment to developing retinal vessels sustained EC-PC dissociations and BRB breakdown in adult mouse retinas, reproducing characteristic features of DR such as hyperpermeability, hypoperfusion, and neoangiogenesis. Notably, PC depletion directly induced inflammatory responses in ECs and perivascular infiltration of macrophages, whereby macrophage-derived VEGF and placental growth factor (PlGF) activated VEGFR1 in macrophages and VEGFR2 in ECs. Moreover, angiopoietin-2 (Angpt2) upregulation and Tie1 downregulation activated FOXO1 in PC-free ECs locally at the leaky aneurysms. This cycle of vessel damage was shut down by simultaneously blocking VEGF, PlGF, and Angpt2, thus restoring the BRB integrity. Together, our model provides new opportunities for identifying the sequential events triggered by PC deficiency, not only in DR, but also in various neurological disorders.

Retinal Hemodynamics Seen on Optical Coherence Tomography Angiography Before and After Treatment of Retinal Vein Occlusion.

PURPOSE: This study evaluates the retinal hemodynamics using optical coherence tomography angiography (OCTA) before and after anti-vascular endothelial growth factor (VEGF) therapy in patients with macular edema associated with retinal vein occlusion (RVO). METHODS: Twelve patients (23 eyes; mean age, 64 years) were included (eight eyes with branch RVO, four with central RVO, and 11 unaffected fellow eyes. The best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured before and 6 months after treatment. The foveal avascular zone (FAZ), nonperfused areas (NPAs), and flow area were evaluated with OCTA before and after treatment. RESULTS: The BCVA and CRT improved significantly after treatment. In eyes with RVO, the baseline FAZ in the retinal deep capillary layer was larger than in fellow eyes and enlarged in the retinal superficial and deep capillary layers after therapy; NPAs decreased after therapy, especially in the retinal deep capillary layer; and the baseline flow area was smaller than in fellow eyes and improved after therapy, especially in the retinal deep capillary layer. CONCLUSIONS: Optical coherence tomography angiography can evaluate the retinal hemodynamics in patients with RVOs. Anti-VEGF therapy reduced the NPA size and improved retinal blood flow, especially in the retinal deep layer. The current results suggested that anti-VEGF therapy might improve retinal deep ischemia in patients with RVO in the retinal deep layer, which is abundant in capillaries.

Microaneurysms cause refractory macular edema in branch retinal vein occlusion.

Intravitreal anti-vascular endothelial growth factor (VEGF) agents can treat macular edema (ME) in branch retinal vein occlusion (BRVO). However, refractory ME, the mechanism of which is not well elucidated, occurs frequently. Sixty-six eyes with ME secondary to BRVO were enrolled in this retrospective observational case-control study. Twenty eyes received a sub-Tenon's capsule injection of triamcinolone acetonide (STTA), 22 eyes an intravitreal anti-VEGF injection (ranibizumab), 16 eyes were switched from STTA to ranibizumab, 4 eyes underwent vitrectomy, and 4 eyes were untreated. Multiple regression analysis and multivariate logistic regression analysis were conducted, respectively, to identify independent predictors of visual acuity (VA) prognosis and risk factors for refractory ME longer than 1 year. The mechanism of refractory ME and therapeutic approaches for identified risk factors also were investigated. Thirty-four (52%) eyes had refractory ME for over 1 year. Microaneurysms were identified as risk factors for refractory ME, leading to poor final VA. Ranibizumab suppressed microaneurysm formation and refractory ME, with early administration more effective. For already formed microaneurysms, laser photocoagulation reduced additional treatments. Microaneurysms may cause refractory ME in BRVO. Alternative therapy to suppress microaneurysms should be considered to prevent refractory ME in patients with BRVO.