Early-Onset Ocular Motor Cranial Neuropathy Is a Strong Predictor of Dementia: A Nationwide, Population-Based Cohort Study.

PURPOSE: To assess the risk of dementia in individuals with newly diagnosed ocular motor cranial neuropathy (OMCN). DESIGN: A nationwide, population-based cohort study using authenticated data from the Korean National Health Insurance Service (KNHIS). PARTICIPANTS: This study included 60 781 patients with OMCN who received a diagnosis between 2010 and 2017 and were followed up through 2018, with an average follow-up of 3.37 ± 2.21 years with a 1-year lag. After excluding patients with disease related to oculomotor dysfunction preceding the OMCN diagnosis, a total of 52 076 patients with OMCN were established. Of these, 23 642 patients who had participated in the National Health Screening Program (NHSP) within 2 years before the OMCN diagnosis were included. After applying the exclusion criteria, the final cohort comprised 19 243 patients and 96 215 age and sex-matched control participants without OMCN. METHODS: We identified patients with newly diagnosed OMCN in the KNHIS database and collected participant characteristics from the health checkup records of the NHSP. The study end point was determined by the first claim with a dementia diagnostic code and antidementia medications. The association of OMCN with dementia risk was examined using Cox proportional hazards regression analysis, adjusting for potential confounding factors. MAIN OUTCOME MEASURES: The main outcome measures were hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) development in patients with OMCN relative to those without OMCN. RESULTS: Patients with newly diagnosed OMCN demonstrated higher metabolic comorbidities than those without OMCN. New OMCN was associated with an elevated risk of ACD (HR, 1.203; 95% CI, 1.113-1.300), AD (HR, 1.137; 95% CI, 1.041-1.243), and VaD (HR, 1.583; 95% CI, 1.286-1.948), independent of potential confounding factors. The younger age groups exhibited a stronger association between OMCN and ACD (HR, 8.690 [< 50 years] vs. 1.192 [≥ 50 years]; P = 0.0004; HR, 2.517 [< 65 years] vs. 1.099 [≥ 65 years]; P < 0.0001). CONCLUSIONS: This nationwide population-based study assessed the association between OMCN and dementia risk. Our results demonstrated a robust relationship between OMCN and the risk of dementia, particularly in the younger population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis.

RATIONALE: The Hippo pathway governs cellular differentiation, morphogenesis, and homeostasis, but how it regulates these processes in lymphatic vessels is unknown. OBJECTIVE: We aimed to reveal the role of the final effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), in lymphatic endothelial cell (LEC) differentiation, morphogenesis, and homeostasis. METHODS AND RESULTS: During mouse embryonic development, LEC-specific depletion of Yap/Taz disturbed both plexus patterning and valve initiation with upregulated Prox1 (prospero homeobox 1). Conversely, LEC-specific YAP/TAZ hyperactivation impaired lymphatic specification and restricted lymphatic sprouting with profoundly downregulated Prox1. Notably, lymphatic YAP/TAZ depletion or hyperactivation aggravated or attenuated pathological lymphangiogenesis in mouse cornea. Mechanistically, VEGF (vascular endothelial growth factor)-C activated canonical Hippo signaling pathway in LECs. Indeed, repression of PROX1 transcription by YAP/TAZ hyperactivation was mediated by recruitment of NuRD (nucleosome remodeling and histone deacetylase) complex and endogenous binding activity of TEAD (TEA domain family members) to the PROX1 promoter. Furthermore, YAP/TAZ hyperactivation enhanced MYC signaling and inhibited CDKN1C, leading to cell cycle dysregulation and aberrant proliferation. CONCLUSIONS: We find that YAP and TAZ play promoting roles in remodeling lymphatic plexus patterning and postnatal lymphatic valve maintenance by negatively regulating Prox1 expression. We further show that YAP and TAZ act as plastic regulators of lymphatic identity and define the Hippo signaling-mediated PROX1 transcriptional programing as a novel dynamic checkpoint underlying LEC plasticity and pathophysiology.

Structural profile of dome-shaped macula in degenerative myopia and its association with macular disorders.

BACKGROUND: To evaluate the detailed structural profile of dome-shaped macula and its association with myopic macular complications. METHODS: This retrospective study included 147 eyes of 93 patients who were diagnosed with degenerative myopia. The height of the scleral dome and diameter of the dome base were measured via enhanced depth imaging optical coherence tomography images with 1:1 µm setting. Spherical equivalent and best-corrected visual acuity were compared in eyes with and without dome-shaped macula. In eyes with dome-shaped macula, the height and diameter of the dome were compared in eyes with and without myopic macular complications including choroidal neovascularization, myopic foveoschisis, and macular hole. RESULTS: Dome-shaped macula was noted in 60 eyes (40.8%) of 42 patients. The mean height of the dome in the eyes with dome-shaped macula was 126.5 ± 69.4 µm (53 to 345 µm) and the mean diameter of the dome base was 2862.1 ± 794.9 µm (1567 µm to 4886 µm). In comparing eyes with and without dome-shaped macula, eyes with dome-shaped macula had higher myopia (- 13.7 diopters vs - 12.1 diopters, P = 0.022). There was no difference in visual acuity in eyes with or without dome-shaped macula (P = 0.132). The height and diameter of the dome in eyes with and without myopic foveoschisis were 78.6 ± 20.6 µm and 134.9 ± 71.6 µm, 2499.2 ± 303.1 µm and 2969.3 ± 645.7 µm, respectively (P = 0.009 and P = 0.017). However, the height and diameter of the dome were not related to the incidence of a macular hole (P = 0.324 and P = 0.605) and choroidal neovascularization (P = 0.835 and P = 0.905). CONCLUSIONS: The prevalence of dome-shaped macula was about 40% in the eyes with degenerative myopia. Although dome-shaped macula was associated with higher degrees of myopia, a prominent dome seemed to be protective against myopic foveoschisis.

Comparison of outcomes after topography-modified refraction versus wavefront-optimized versus manifest topography-guided LASIK.

BACKGROUND: To compare the outcomes of myopia and myopic astigmatism corrected with topography-modified refraction laser in situ keratomileusis (TMR-LASIK), wavefront-optimized (WFO) LASIK, and topography-guided (TG) LASIK with a correction target based on the manifest refraction (manifest TG-LASIK). METHODS: This observational, retrospective cohort study included patients who underwent LASIK using the WaveLight® EX500 excimer laser to correct myopia and myopic astigmatism between August 2016 and July 2017. Patients who underwent TMR-LASIK (85 patients), WFO-LASIK (70 patients), or manifest TG-LASIK (40 patients) were enrolled, and only one eye from each patient was analyzed. All participants underwent measurement of the uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (BCVA), manifest refraction, vector analysis of astigmatic change, corneal topography, and corneal wavefront analysis at baseline and at every posttreatment visit. RESULTS: Three months postoperatively, a UDVA of 0.0 logMAR or better and manifest refraction spherical equivalent (MRSE) within ±0.5 diopters (D) did not differ across the TMR-, WFO-, and manifest TG-LASIK groups. However, the residual cylinder in the TMR group was significantly larger than that in the WFO and manifest TG groups. The magnitude of error in the TMR group measured using astigmatism vector analysis was significantly higher than that in the WFO and manifest TG groups. CONCLUSIONS: Although these three LASIK platforms achieved the predicted surgical outcomes, TMR-LASIK overcorrected astigmatism and showed a higher residual postoperative astigmatism compared with WFO- and manifest TG-LASIK.

Postural effects on intraocular pressure and ocular perfusion pressure in patients with non-arteritic anterior ischemic optic neuropathy.

BACKGROUND: To investigate postural effects on intraocular pressure (IOP) and ocular perfusion pressure (OPP) in patients with non-arteritic ischemic optic neuropathy (NAION). METHODS: IOP and blood pressure (BP) were measured in 20 patients with unilateral NAION 10 min after changing to each of the following positions sequentially: sitting, supine, right lateral decubitus position (LDP), supine, left LDP, and supine. IOP was measured using a rebound tonometer and OPP was calculated using formulas based on mean BP. The dependent LDP (DLDP) was defined as the position when the eye of interest (affected or unaffected eye) was placed on the dependent side in the LDP. RESULTS: IOPs were significantly higher (P = 0.020) and OPPs were significantly lower (P = 0.041) in the affected eye compare with the unaffected eye, with the affected eye in DLDP. Compared with the mean IOP of the unaffected eyes, the mean IOP of the affected eyes increased significantly (+2.9 ± 4.4 versus +0.7 ± 3.1 mmHg, respectively; P = 0.003) and the mean OPP decreased significantly (-6.7 ± 9.4 versus -4.9 ± 8.0 mmHg, respectively; P = 0.022) after changing positions from supine to DLDP. In addition, changing position from supine to DLDP showed significantly larger absolute changes in IOP (4.13 ± 3.19 mmHg versus 2.51 ± 1.92 mmHg, respectively; P = 0.004) and OPP (9.86 ± 5.69 mmHg versus 7.50 ± 5.49 mmHg, respectively; P = 0.009) in the affected eye compared with the unaffected eye. In the affected eye, there was a significant positive correlation between absolute change in IOP and OPP when changing position from supine to DLDP (Rho = 0.512, P = 0.021). CONCLUSIONS: A postural change from supine to DLDP caused significant fluctuations in IOP and OPP of the affected eye, and may significantly increase IOP and decrease OPP. Posture-induced IOP changes may be a predisposing factor for NAION development.

Combined intravitreal bevacizumab injection and zone I sparing laser photocoagulation in patients with zone I retinopathy of prematurity.

PURPOSE: To investigate the anatomical outcome of combined intravitreal bevacizumab injection and Zone I sparing laser ablation in patients with Type 1 retinopathy of prematurity in Zone I. METHODS: The medical records of consecutive 18 eyes of 10 infants, who underwent combined intravitreal bevacizumab (0.25 mg) injection and Zone I sparing laser ablation for the treatment of Type 1 retinopathy of prematurity in Zone I, were retrospectively reviewed. Laser photocoagulation was performed on the avascular retina anterior to the margin of Zone I extending to the ora serrata. Anatomical outcomes including progression to stage 4/5, macular changes, and vitreous organization were reviewed. RESULTS: The mean gestational age at birth and the birth weight of included patients were 24.0 weeks and 628 g, respectively. The timing of bevacizumab injection ranged from postmenstrual age 33(+2) to 35 weeks (mean, 34.3 weeks). Postmenstrual age at last follow-up ranged from 74(+6) to 107(+1) weeks (mean, 83.6 weeks). All 18 eyes demonstrated prompt regression of neovascular pathology and plus disease without recurrence. Previously avascular Zone I retina was vascularized in all eyes after the treatment. All eyes showed excellent anatomical outcome with intact macula, but one eye showed mild vitreous organization above the vascular/avascular junction. CONCLUSION: Combined intravitreal bevacizumab injection and Zone I sparing laser ablation for Type 1 retinopathy of prematurity in Zone I seem to be effective treatment options. Possible advantages include lower dose of anti-vascular endothelial growth factor, less recurrence than monotherapy, and preservation of central visual field.

Intraocular Lens Refractive Index and Its Impact on External Surface Reflections.

PURPOSE: To determine and compare the origin of the external surface reflections produced by commonly used intraocular lenses (IOLs). METHODS: The specular reflection taking place at the anterior surface of eight types of IOLs (IOL power = 22.00 diopters [D]) with different refractive indices (RIs), optical design, and ultraviolet and blue light-filtering function were measured. The experimental set-up included a laser beam light source (3.5 mW, 532 nm) and a saline-filled model eye containing the IOL to be examined. External surface reflections were measured using a power meter, and the IOL surface reflectance (%) was compared among the eight IOLs investigated. RESULTS: External reflections from the anterior surface of the studied implants increased as the RI of the IOL material increased. The IOL models composed of high RI material (RI = 1.56 ± 0.02) were found to have a more than threefold higher external surface reflections compared to those with low RI (RI = 1.45 ± 0.02). Ultraviolet or blue light-filtering functions showed no significant correlation with the external reflectance. CONCLUSIONS: IOLs with a high RI are associated with external surface reflections that are more than threefold higher than those with lower RI. The "cat's eye" phenomenon seen in pseudophakic eyes by an outside observer strongly depends on the RI, but is independent of the filter incorporated in the IOL. [J Refract Surg. 2021;37(6):398-402.].

Control of endothelial quiescence by FOXO-regulated metabolites.

Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.

FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure.

The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor Foxc2 in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. Foxc2 loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2. Commensal microbiota depletion dampened systemic pro-inflammatory cytokine levels, corrected intestinal lymphatic dysfunction, and improved survival. Foxc2 loss skewed the specialization of lymphatic endothelial subsets, leading to populations with mixed, pro-fibrotic identities and to emergence of lymph node-like endothelial cells. Our study uncovers a cross-talk between lymphatic vascular function and commensal microbiota, provides single-cell atlas of lymphatic endothelial subtypes, and reveals organ-specific and systemic effects of dysfunctional lymphatics. These effects potentially contribute to the pathogenesis of diseases, such as inflammatory bowel disease, cancer, or lymphedema.

Resolution of Corneal Fibrosis After Descemet's Stripping Automated Endothelial Keratoplasty: A Case Report.

PURPOSE: To report the resolution of anterior corneal fibrosis after Descemet's stripping automated endothelial keratoplasty (DSAEK), in a patient with chronic corneal edema and anterior stromal scarring. METHODS: A 63-year-old woman, with a history of Fuchs endothelial dystrophy, presented with increasing discomfort and gradual visual loss in her right eye. Clinical examination revealed long-standing bullous keratopathy accompanied by marked subepithelial fibrosis (SEF). Based on the low postoperative visual potential due to glaucomatous optic neuropathy, we decided to proceed with DSAEK. RESULTS: During the follow-up period, SEF was found to gradually resolve. Corneal clarity was restored and an improvement in visual acuity was observed up to 12 months after surgery. CONCLUSION: DSAEK alone may represent an effective therapeutic option for the restoration of impaired corneal clarity in patients with long-standing corneal edema and concomitant anterior subepithelial scarring.

Enhanced orbital adipogenesis in a mouse model of T-cell-mediated autoimmunity, zymosan A-treated SKG mice: Implications for Graves' ophthalmopathy.

Inflammation and remodelling of orbital tissue associated with enhanced adipogenesis commonly occur in Graves' ophthalmopathy (GO), however, the underlying mechanisms that link immune cells and adipocytes in orbital inflammation are not well-known. The primary aim of this study was to elucidate how a genetically determined shift in the T-cell repertoire toward self-reactive T-cells could drive orbital adipogenesis. To induce the T-cell-mediated autoimmune response, SKG mice were intraperitoneally injected with zymosan A once at 8 weeks of age. After three months, orbital magnetic resonance imaging (MRI), histopathologic studies, and in vitro analyses were performed to evaluate inflammation and adipogenesis. The eyes of the zymosan A-treated SKG mice displayed proptosis and blepharitis. A detailed analysis of orbital adipose tissue showed enhanced orbital adipogenesis and cellular infiltration compared to controls. In addition, increased secretion of adipokines and other cytokines in the periorbital tissue was observed, together with elevated serum concentration of inflammatory cytokines. Orbital adipogenesis was enhanced in zymosan A-treated SKG mice, a novel mouse model for GO-like inflammatory adipose phenotypes most likely induced by T-cell mediated autoimmune responses. This mouse model gives us the opportunity to examine the underlying molecular mechanisms of enhanced adipogenesis in GO, ultimately providing a potential therapeutic target alternative to conventional GO treatment.

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice.

Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs.

Predictive factors associated with axial length growth and myopia progression in orthokeratology.

PURPOSE: To investigate the factors affecting axial length (AXL) growth and myopia progression in orthokeratology. METHODS: This prospective, observational study enrolled 28 new orthokeratology lens wearers from a contact lens clinic between March 2016 and March 2017. Among them, 32 eyes of 17 wearers who completed one year of follow-up were finally analyzed. All participants underwent central (C) and peripheral (nasal 30° [N30] and temporal 30° [T30]) AXL measurements as well as central and peripheral refraction, ocular aberrations, and corneal topography at baseline and every posttreatment visit. A generalized estimating equation (GEE) was used to assess the associations between AXL change and all independent variables in both eyes. RESULTS: The mean central AXL was 24.21 ± 0.60 mm and the mean baseline central spherical equivalent refractive error (SER) was -2.43 ± 0.97 diopters (D). Among all parameters that were significantly associated with AXL change in univariable GEE analyses, the baseline difference in AXL between C and N30 (ß = -0.213, p < 0.001), baseline SER (ß = -0.040, p < 0.033), posttreatment coma (ß = -0.291, p < 0.031), third-order higher-order aberrations (HOAs) (ß = -0.482, p < 0.001), and changes in second-order aberrations (ß = 0.025, p = 0.027) at one year of follow-up were identified as significant factors in multivariable GEE analysis. CONCLUSIONS: The inhibition of AXL elongation and myopia progression in orthokeratology lens wear is significantly associated with the peripheral myopization and asymmetric optical changes mostly induced by third-order HOAs.

Topography-guided versus wavefront-optimized laser in situ keratomileusis for myopia: Surgical outcomes.

PURPOSE: To compare the outcomes of topography-guided and wavefront-optimized surgery in patients having laser in situ keratomileusis (LASIK) for myopia. SETTING: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, and BALGEUN-EYE21 Operation Center, Gwangju, South Korea. DESIGN: Prospective case study. METHODS: Patients had topography-guided LASIK in 1 eye and wavefront-optimized LASIK in the contralateral eye using Contoura Vision software and the WaveLight EX500 excimer laser. Refractive and visual outcomes were analyzed 3 months postoperatively. RESULTS: The study comprised 43 patients. In both groups, the postoperative uncorrected distance visual acuity (UDVA) was 0.0 logarithm of the minimum angle of resolution or better in 90.7% of eyes and the residual spherical equivalent (SE) refractive error was ±0.75 diopter (D) in 81.4% of eyes. The UDVA, residual SE refractive error, and astigmatism did not differ significantly between the 2 groups. There was significant induction of higher-order aberrations (HOAs) in both groups, although corneal coma and trefoil did not increase and ocular trefoil decreased significantly in the topography-guided group (P = .038). However, in the wavefront-optimized group, corneal coma and trefoil increased significantly (P < .001 and P = .046, respectively) and ocular trefoil did not change significantly. In addition, topography-guided LASIK induced significantly fewer corneal total HOAs (P < .001), coma (P < .001), and trefoil (P = .020) than wavefront-optimized LASIK. CONCLUSION: Although both topography-guided LASIK and wavefront-optimized LASIK safely and effectively achieved the predicted refractive and visual outcomes, topography-guided LASIK induced fewer HOAs and significantly decreased ocular trefoil, corneal total HOAs, and coma.

Retinal Vein Occlusion is Associated with Low Blood High-Density Lipoprotein Cholesterol: A Nationwide Cohort Study.

PURPOSE: To investigate association between the development of retinal vein occlusion (RVO) and blood high-density lipoprotein cholesterol (HDL-C). DESIGN: A retrospective, nationwide, population-based cohort study. METHODS: This study was set in the Republic of Korea and included 23,149,403 people ≥20 years of age who underwent the Korean National Health Screening Program examination between January 2009 and December 2012. Among them, the RVO group was composed of patients with an initial diagnosis of RVO made between 2009 and 2015 (n = 117,639). The earliest claim with an RVO diagnostic code was considered as the incident time. The predictive value of HDL-C level for RVO was analyzed using hazard ratios. The primary outcome measure was the incident cases of RVO. RESULTS: Subjects with RVO were generally older; had high body mass index, waist circumference, fasting blood glucose, blood pressure, total and low-density lipoprotein cholesterol, and triglyceride values, and low glomerular filtration rate and HDL-C values; and were more likely to experience diabetes mellitus and hypertension compared with the non-RVO group. The fully adjusted hazard ratio of RVO was 1.12 (95% confidence interval 1.10-1.14) in the lowest quartile of HDL-C versus in the highest quartile. The association between the development of RVO and HDL-C was higher those with a younger age, male sex, current smoking habit, diabetes mellitus, and hypercholesterolemia. In addition, we observed a significant synergistic effect of low HDL-C level with obesity and hypertension. CONCLUSION: This is the first nationwide population-based epidemiologic study evaluating the association between HDL-C level and the risk of RVO development. A significant association between low HDL-C and RVO development was found.

Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration.

Choriocapillary loss is a major cause of neovascular age-related macular degeneration (NV-AMD). Although vascular endothelial growth factor (VEGF) blockade for NV-AMD has shown beneficial outcomes, unmet medical needs for patients refractory or tachyphylactic to anti-VEGF therapy exist. In addition, the treatment could exacerbate choriocapillary rarefaction, necessitating advanced treatment for fundamental recovery from NV-AMD. In this study, Tie2 activation by angiopoietin-2-binding and Tie2-activating antibody (ABTAA) presents a therapeutic strategy for NV-AMD. Conditional Tie2 deletion impeded choriocapillary maintenance, rendering eyes susceptible to NV-AMD development. Moreover, in a NV-AMD mouse model, ABTAA not only suppressed choroidal neovascularization (CNV) and vascular leakage but also regenerated the choriocapillaris and relieved hypoxia. Conversely, VEGF blockade degenerated the choriocapillaris and exacerbated hypoxia, although it suppressed CNV and vascular leakage. Together, we establish that angiopoietin-Tie2 signaling is critical for choriocapillary maintenance and that ABTAA represents an alternative, combinative therapeutic strategy for NV-AMD by alleviating anti-VEGF adverse effects.

Plastic roles of pericytes in the blood-retinal barrier.

The blood-retinal barrier (BRB) consists of tightly interconnected capillary endothelial cells covered with pericytes and glia, but the role of the pericytes in BRB regulation is not fully understood. Here, we show that platelet-derived growth factor (PDGF)-B/PDGF receptor beta (PDGFRß) signalling is critical in formation and maturation of BRB through active recruitment of pericytes onto growing retinal vessels. Impaired pericyte recruitment to the vessels shows multiple vascular hallmarks of diabetic retinopathy (DR) due to BRB disruption. However, PDGF-B/PDGFRß signalling is expendable for maintaining BRB integrity in adult mice. Although selective pericyte loss in stable adult retinal vessels surprisingly does not cause BRB disintegration, it sensitizes retinal vascular endothelial cells (ECs) to VEGF-A, leading to upregulation of angiopoietin-2 (Ang2) in ECs through FOXO1 activation and triggering a positive feedback that resembles the pathogenesis of DR. Accordingly, either blocking Ang2 or activating Tie2 greatly attenuates BRB breakdown, suggesting potential therapeutic approaches to reduce retinal damages upon DR progression.

YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation.

Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.