Retinal Vascularization Research Articles

Contraceptive Pills and Retinal Vascularization

Contraceptive Pills and Retinal Vascularization

Carvone protects against paclitaxel-induced retinal and optic nerve cytotoxicity: a histopathological study

Purpose: Carvone (CVN) is a natural monoterpene found in essential oils of many aromatic plant species. In this study, we investigated the protective effect of CVN against paclitaxel (PTX)-induced retinal and optic nerve cytotoxicity in rats.Methods: Twenty-four male adult Wistar albino rats (250–400 g) were randomized into four equal groups comprising six animals in each. Group 1 (control group) received intraperitoneal (i.p.) saline solution (0.5 mL/200 g) weekly for 4 weeks. Group 2 received i.p. CVN [(S)-(+)- CVN, (5S)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one, C10H14, 25 mg/kg], while Group 3 received i.p. PTX (5 mg/kg) weekly for 4 weeks. Group 4 received i.p. CVN (25 mg/kg) 30 min after i.p. PTX (5 mg/kg) weekly for 4 weeks. At the end of the experimental period, retinal and optic nerve tissues were evaluated histopathologically.Results: All retinal specimens in control and CVN groups were histopathologically normal. In PTX group all eyes (6/6) demonstrated increased retinal vascularity and rosette-like structures in the outer nuclear layer, while in PTX-CVN group all eyes (6/6) demonstrated normal retinal vascularity and absence of rosette-like structures. All optic nerve specimens in control and CVN groups were histopathologically normal. In PTX group all eyes (6/6) demonstrated severe vacuolization and decrease in the number of astrocytes and oligodendrocytes, while 3 eyes (3/6) demonstrated marked single cell necrosis. In PTX-CVN group, 4 eyes (4/6) demonstrated moderate vacuolization while, 2 eyes (2/6) had none. Compared with PTX group, 1 eye (1/6) in PTX-CVN group demonstrated a decrease in numbers of astrocytes and oligodendrocytes while 5 eyes (5/6) were normal. No remarkable single cell necrosis was observed in PTX-CVN group.Conclusions: Our histopathological findings demonstrated the potential protective role of CVN against PTX-induced retinal and optic nerve cytotoxicity. CVN might be a promising molecule in counteracting oxidative stress-based cytotoxicity in the field of retinal and optic nerve disorders.

Speed of Retinal Vascularization in Retinopathy of Prematurity: Risk and Protective Factors.

Objective The objective was to study the risk and protective factors involved in retinal vascular development of preterm infants with retinopathy of prematurity. Methods Between 2000 and 2017, 185 preterm infants were included in the protocol for retinopathy of prematurity. Risk factors associated with speed of retinal vascularization <0.5 disc diameter/week were studied in each of them. Results The statistically significant variables related to retinal vascular development <0.5 DD/w were intubation days, degree 3 of bronchopulmonary dysplasia, weight gain at 4-6 weeks, avascular temporal area, gestational age, number of transfusions, sepsis, number of risk factors, apnea at birth, presence of ductus arteriosus, and days of continuous positive airway pressure therapy. After the multivariate logistic regression analysis, only three variables were found to be significant: intubation days (p=0.005), degree 3 of bronchopulmonary dysplasia (p=0.022), and weight gain at 4–6 weeks (p=0.031). Conclusion In retinopathy of prematurity, degree 3 of bronchopulmonary dysplasia and intubation days cause delayed retinal vascular development, whereas greater postnatal weight gain favors an appropriate rate of retinal vascularization.

Blood-retina barrier failure and vision loss in neuron-specific degeneration.

Changes in neuronal activity alter blood flow to match energy demand with the supply of oxygen and nutrients. This functional hyperemia is maintained by interactions between neurons, vascular cells, and glia. However, how changing neuronal activity prevalent at the onset of neurodegenerative disease affects neurovascular elements is unclear. Here, in mice with photoreceptor degeneration, a model of neuron-specific dysfunction, we combined assessment of visual function, neurovascular unit structure, and the blood-retina barrier permeability. We found that the rod loss paralleled remodeling of the neurovascular unit, comprised of photoreceptors, retinal pigment epithelium, and Muller glia. When significant visual function was still present, blood flow became disrupted and blood-retina barrier began to fail, facilitating cone loss and vision decline. Thus, in contrast to the established view, vascular deficit in neuronal degeneration is not a late consequence of neuronal dysfunction, but is present early in the course of disease. These findings further establish the importance of vascular deficit and blood retina barrier function in neuron-specific loss, and highlight it as a target for early therapeutic intervention.

MON-486 Prolactin Reduces the Hyperoxia-Induced Inhibition of Retinal Neovascularization in Newborn Mice

Retinopathy of prematurity (ROP) is a potentially blinding retinal neovascular disease. Prolactin (PRL) circulating levels are higher in ROP than in control patients and such imbalance is a predictive risk variable for ROP that may impact disease progression (Zepeda-Romero et al. Pediatric Res 2017). PRL accesses the retina from the systemic circulation and is pro-angiogenic but can be cleaved into anti-angiogenic PRL fragments (vasoinhibin). Like preterm infants, newborn mice have incomplete retinal vascularization at birth and exposure to high oxygen, mimicking supplemental oxygen given to premature infants for respiratory care, induces the loss of new blood vessels eventually leading to hypoxia-induced retinal neovascularization. Here, we have investigated whether raising circulating PRL levels modifies the neovascularization of the retina of newborn mice exposed to high-oxygen. Neovascularization was assessed in mice throughout the first 8 days after birth in flat-mounted retinas immunostained for blood vessels. At postnatal day 1 (P1) the retina is almost devoid of blood vessels, which originate from the optic nerve and migrate radially reaching the periphery at P8. Exposure of P6 mice and nursing mothers to hyperoxia (75% oxygen) inhibited retinal vessel growth as determined by a significant (p<0.01) 50% reduction in retinal vascular density and expression of the endothelial cell markers, CD31 and VEGF receptor 2. Treatment with PRL (2 µg/g i.p. twice a day from P5 to P8) elevated PRL levels in serum (>300 ng/ml) and reduced hyperoxia-induced inhibition of retinal neovascularization, as revealed by a significant increase (p<0.03) in retinal vascular density and expression of endothelial cell markers. Current studies are addressing whether the pro-angiogenic effect of PRL is favored by its lower retinal conversion to vasoinhibin under hyperoxic conditions. These findings indicate that high levels of systemic PRL increase the vascularization of the neonatal mouse retina under conditions mimicking an early phase of ROP and support clinical studies suggesting the impact of PRL on disease progression. Supported by CONACYT grant 289568.

Optical Coherence Tomography Angiography Quantitative Assessment of Exercise-Induced Variations in Retinal Vascular Plexa of Healthy Subjects.

To assess the variations induced by exercise in retinal vascular density (VD), foveal avascular zone (FAZ) area, and fractal dimension (FD) at the superficial (SCP) and deep (DCP) capillary plexa in healthy subjects by means of optical coherence tomography angiography (OCT-A). Consecutive healthy subjects were prospectively included into two groups, ranging in age from 18 to 29 years for group 1 and from 30 to 40 years for group 2. Data from 3 × 3-mm OCT-A acquisition centered on the macula at SCP and DCP (VD, FAZ area, and FD), heart rate, and systolic-diastolic blood pressure were collected before and after a 20-minute standardized physical exercise on a stationary bicycle. Both eyes of 32 healthy volunteers were prospectively included (15 in group 1 and 17 in group 2). Mean age was 27 ± 7 years. In the overall analysis and for each group, a decrease of VD at the level of SCP and an increase of FD at the level of DCP were significant after exercise. A significant correlation was found between these modifications of retinal vascularization and the increase of systolic blood pressure induced by exercise. All cardiovascular parameters increased significantly with exercise. No significant difference was found between the two groups, and no incident was reported. A significant correlation was established between systemic cardiovascular modifications (reflected by systolic blood pressure) and local retinal vascularization changes at SCP during exercise. A rest period might be recommended before OCT-A data acquisition, as modifications of cardiovascular parameters could distort retinal vascular data.

Protective effects of different bile acids against pathological neovascularization

Emerging evidence suggest that the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine (TUDCA) conjugates, possess neuroprotective and vasculoprotective properties and may exert beneficial effects in a number of neovascular diseases including ischemic retinopathy such as retinopathy of prematurity (ROP). However, the direct activity of UDCA or TUDCA in the treatment of retinal neovascularization has not been previously investigated. Herein, we studied the effects of different bile acids on in vitro angiogenesis in human retinal endothelial cells (HuREC) and retinal vascularization in vivo using the mouse model of oxygen induced retinopathy (OIR), an experimental model of ROP. HuREC were treated with 20 ng/ml of VEGF and/or different doses (10–500 μM) of UDCA or TUDCA for different times. Angiogenic responses were evaluated using tube formation assay. Treatment of HuREC with VEGF significantly induced time dependent tube formation. UDCA dose‐dependently halted VEGF‐induced tube formation, whereas TUDCA had no effect. For the in vivo studies, mice were subjected to OIR and treated with UDCA and TUDCA (administered i.p.) from days P12–P17 (the neovascular stages). Isolectin B4 staining on flat mounted retinal preparations was performed at P17 to evaluate retinal vessel growth and distribution. The results of this analysis revealed that UDCA in the OIR mice halted pathological neovascularization, but did not alter normal vascularization. On the contrary, treatment of the mice with TUDCA failed to block retinal neovascularization, thus confirming the in vitro data. In summary, here we have shown that the bile acids UCDA and TUCDA possess differential ability to modulate VEGF‐mediated angiogenesis effects on HuREC and on retinal pathological neovascularization in vivo. The results of studies support the hypothesis that UDCA could be a potential therapeutic option for ROP as it exerts protection even by systemic administration and does not alter normal progression of vessel formation.Support or Funding InformationThis study is supported by R03HD097660‐01.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Early Diagnosis and Management of Aggressive Posterior Vitreoretinopathy Presenting in Premature Neonates.

Aggressive posterior vitreoretinopathy (APVR) manifests with a broad area of retinal avascularity, progressive neovascularization, and/or tractional retinal detachment during the neonatal period. A multicenter, retrospective, observational, consecutive case series study was performed to evaluate the retinal findings and structural retinal outcomes in patients treated for APVR within the first 3 months of life. Three premature neonates with a non-retinopathy of prematurity (ROP) APVR identified during routine ROP screening exams exhibited relatively severe, rapidly progressive retinal vascular abnormalities. Immediate laser photocoagulation of the avascular retina and vitrectomy for traction retinal detachment within several days to weeks improved or stabilized the retinal anatomy in all cases. This series describes clinical features in APVR in premature infants and suggests that early diagnosis and intervention may mitigate the typical aggressive course and poor prognosis of this condition. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:201-207.].

PO2 Profiles in the Retina of the Hemoglobin‐less Icefishes

The retina of vertebrates has one of the highest O2 demands and requires a constant O2 supply. Four general types of retinal circulations have been described for O2 delivery in extant vertebrates: 1) sole reliance on the choriocapillaris; 2) capillaries penetrating the retina; 3) capillarization of the inner side of the retina; and 4) O2 secretion. Oxygen secretion is based on acid secretion into the blood resulting in a potent unloading of O2 from so‐called Root effect hemoglobins (Hb), which is augmented by venous to arterial O2 diffusion in a vascular rete lining the back side of the retina. This choroid rete mirabile (CRM) allows O2 delivery at super‐atmospheric pressure in the avascular retina of some fishes that have the thickest retinae and some of the largest eyes (relative to body size) of all extant vertebrates. The suborder Notothenioidei, which consists of Antarctic and sub‐Antarctic fishes, provides a model system to unravel how the interactions between Hb function and retinal vascularity evolved to produce modern fish eyes. While several phyletically basal notothenioids have been shown to display similar ocular arrangements as in other Perciform species containing a CRM, more phyletically derived notothenioids have highly reduced CRM or have lost it completely. Of particular interest are the species of the family Channichthyidae, icefishes, that are unique among adult vertebrates in possessing pale white blood containing only few vestigial immature erythrocytes and no Hb. Without Hb, O2 secretion is not functional, and icefishes have been demonstrated to possess heavily increased pre‐retinal capillarization most probably to maintain retinal oxygenation and preserve large eyes and thick retinae. However, whether available O2 at different retinal levels actually follows the degree of vascularization has not been tested.Using thin O2 sensors, we measured profiles of partial pressure of O2 (PO2) in the retina of six species of icefishes, two species of related, but red‐blooded dragonfishes (Bathydraconidae), and four species of more distantly related notothens (Nototheniidae). Arterial PO2 was statistically significantly higher in icefishes than in notothens [t‐test; p = 0.0066 (n = 3); PaO2 = 16.64 ± 3.84 kPa in Chaenocephalus aceratus; PaO2 = 4.42 ± 1.40 kPa in Notothenia coriiceps]. In general, pre‐retinal PO2 was high in icefishes (19.20 ± 6.35 kPa in C. aceratus), approaching the theoretical O2 solubility limit without O2 secretion. The PO2 level decreased towards the outer portion of the retina, but with a small peak on the choroid side of the retina, possibly due to a vestigial choriocapillaris. In notothens displaying Root effect, pre‐retinal PO2 was slightly lower (12.07 ± 5.12 kPa in N. coriiceps) but increased to a super‐atmospheric level on the outer portion of the retina (52.25 ± 32.46 kPa in N. coriiceps).Our results demonstrate that retinal PO2 is dictated by vascularization in the Hb‐deprived icefishes, leading to a unique reversal in the retinal oxygen profile.Support or Funding InformationUS National Science Foundation grant PLR‐1444167Carlsberg FoundationVelux FoundationsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Norrin maintains malignancy of gastric cancer cells in part through activating AKT signaling

Human tumorigenesis resembles embryogenesis by aberrant activation of several developmental pathways including Wnt/β-catenin signaling. Norrin is an atypical ligand for Frizzled receptor that is preferentially expressed in the endothelium to promote retinal vascularization during development. However, its expression pattern and potential roles in human cancers remain unclear. Here we report that Norrin expression is elevated in the parenchymal cells, but not endothelial cells, in gastric cancer (GC). Moreover, Norrin is required for growth and invasion of GC cells and its expression status is associated with unfavorable outcomes. However, analysis of the TGCA database demonstrates that Norrin expression status is not correlated with key target genes of Wnt/β-catenin signaling. Among several signaling pathways hyperactivated in cancer, Norrin-depleted GC cells also display down-regulated AKT signaling except the canonical Wnt/β-catenin signaling. Consistently, small molecule-induced cytosolic activation of AKT partially rescues the proliferative and invasive capability of Norrin-depleted cells. Together, these findings suggest a novel role of Norrin in gastric tumorigenesis that could be exploited for adjuvant therapy against the deadly malignancy.

Analysis of the Variation of the Retinal Vascularization After a Prolonged Effort

Analysis of the Variation of the Retinal Vascularization After a Prolonged Effort

Assessment of vascular leakage and its development with FFA among patients treated with intravitreal anti-VEGF due to aggressive posterior ROP.

Evaluation of vascular leakage and retinal vascular development with fundus fluorescein angiography for infants diagnosed with aggressive posterior retinopathy of prematurity who underwent intravitreal anti-VEGF treatment. Medical recordings of 30 patients who received RetCam fluorescein angiography during follow-up and had been treated with anti-VEGF on diagnosis of aggressive posterior ROP in the zone I or zone II between the dates of April 2014-January 2017 were evaluated retrospectively. Fifty-nine eyes of 30 patients were included in the study. Mean birth weight was 1145g; gestation week was 28.4. Recurrence occurred in 30.5% of the patients, and 10.1% of them were given a second dose of injection of anti-VEGF. Leakage was detected in 15.3% of the eyes during angiography, and all of these eyes were treated with laser photocoagulation. Evaluation of vascular development revealed that in the temporal, complete retinal vascular development was achieved in only 8% of the eyes. It was detected that complete retinal vascularization was not observed in any of the cases which were given second dose of injection due to recurrence. The patients were distributed into groups according to postmenstrual week taken to angiography as 32 eyes of 16 patients in group 1, 17 eyes of 9 patients in group 2 and 10 eyes of 5 patients in group 3. The vascular leakage rate of group 3 patients was statistically significantly higher (p < 0.05) and vascular development between groups was not statistically significant (p > 0.05). With the initiation of FFA usage in pediatric cases, especially treated with anti-VEGF due to retinopathy of prematurity (ROP), more findings (vascular arrest, leakage, and abnormalities, etc.) are obtained than those achieved via ophthalmoscopic examination. In the light of these findings, early intervention with laser photocoagulation in early stages becomes possible enabling prevention of possible blindness.

A study of risk factors of retinopathy of prematurity in a tertiary care hospital

Introduction: Retinopathy of prematurity (ROP) is a vaso-proliferative disorder of the retina, which principally occurs in premature neonates during vascular development and maturation stage. ROP is multifactorial disorder. Objectives: The purpose of this study is to know the risk factors and their correlation with retinopathy of prematurity. Methods: All neonates born between 28-34 weeks of gestation admitted in NICU, who are under oxygen, were included in the study and screened for ROP. Babies with ocular disorder which interfere with fundus examination and babies who did not complete follow up till complete vascularization of retina were excluded from the study. Results: A total of 95 neonates were studied for ROP. In babies with gestational age between 30 – 32 weeks, 15.4%, 8.5% in the 32 – 35 weeks and none among those born between more than 35 weeks had ROP. About 12.5% of the patients with no PDA and 57.1% of the patients with PDA had retinopathy of prematurity. About 10.8% of the patients with no anemia and 33.3% with anemia had retinopathy of prematurity. This study had shown that 9.6% of the patients without blood transfusion and 36.4% with blood transfusion had retinopathy of prematurity. In this study 10% of the newborns with no thrombocytopenia and 32% with thrombocytopenia had retinopathy of prematurity.Retinopathy is an important complication of prematurity. Conclusion: Timely referral of detected ROP cases for treatment prevents blindness. There is need for the obstetricians, neonatologist and ophthalmologist to work in close co-operation to prevent blindness due to ROP.

Ranibizumab injection and laser photocoagulation to treat type 1 retinopathy of prematurity after 40\u2009weeks post menstrual age: a retrospective case series study

BackgroundType 1 retinopathy of prematurity (ROP) is occasionally observed in preterm infants after the postmenstrual age (PMA) of 40 weeks; however, evidence-based treatment guidelines are largely lacking. In this study, we report the clinical characteristics of preterm infants with type 1 ROP at PMA of > 40 weeks and compare the treatment outcomes of intravitreal ranibizumab (IVR) and laser therapy.MethodsTwenty-seven eyes of 14 infants, primarily treated for type 1 ROP after 40 weeks PMA by IVR (17 eyes in 9 infants) or by laser photocoagulation (10 eyes in 5 infants) were included in this retrospective analysis. The preoperative fundus characteristics and the structural outcomes and additional treatment after 6 months were analyzed.ResultsOf the 27 eyes, 20 eyes (74%) had zone II stage 3 plus disease (+) ROP and 7 eyes had zone II stage 2 + ROP. Seventeen (63%) eyes showed thick fibrous ridges. After primary treatment at 40–48 weeks PMA, ROP regression was observed in a similar proportion of eyes in the IVR and laser groups (88% vs. 70%; p = 0.326); complete vascularization was observed in 24% eyes in the IVR group. Compared to laser group, a higher proportion of eyes in IVR group received additional treatment (IVR group 76% vs. laser group 30%; p = 0.040), for unresolved peripheral avascularity in 11 eyes and ROP progression with fibrotic contraction in 2 eyes after primary IVR.ConclusionPreterm infants with type 1 ROP at > 40 weeks PMA displayed enhanced fibrotic proliferation. Both primary IVR and laser effectively promote ROP regression. Primary IVR cannot guarantee full retinal vascularization but is associated with a risk of fibrotic contraction.

A clinical study of retinopathy of prematurity in neonates in a tertiary care hospital

Background: Retinopathy of prematurity (ROP) is a disease process mostly reported in preterm neonates with a wide spectrum, ranging from mild, transient changes in the retina with regression to severe progressive vasoproliferation, scarring, detachment of retina and blindness. India shares 20% of the world childhood blindness. Besides congenital cataract, congenital glaucoma and ocular injuries, ROP is emerging as one of the important causes of childhood blindness in India.Methods: A cross sectional study was undertaken among all neonates born between 28-34 weeks of gestation admitted in NICU, who are under oxygen, screened for ROP. Babies with ocular disorder which interfere with fundus examination, babies who did not complete follow up till complete vascularisation of retina and babies with congenital retinal abnormalities were excluded from the study.Results: About 13.3% of male children and 18.0% of the female children had retinopathy of prematurity. Among the infants born before 30 weeks, 46.7% had retinopathy of prematurity. In the children with gestational age between 30- 32 weeks, 15.4%, 8.5% in the 32-35 weeks and none among those born between more than 35 weeks. About 27.9% of the newborns with birth weight of less than 1.5kgs and 5.8% of those who had birth weight of 1.5-2.5kgs had retinopathy of prematurity.Conclusions: This study had shown a significant association of retinopathy of prematurity with the low gestational age, birth weight and oxygen therapy. Reducing subsequent post-natal risk factors depends on optimal perinatal and postnatal care, as well as adhering to strict ROP screening guidelines. Recognizing and treating ROP in a timely fashion is critical for achieving the best visual outcome.

Delayed resolution of retinopathy of prematurity

To compare the characteristics of infants whose retinopathy of prematurity (ROP) resolves in <50weeks with those of infants whose ROP resolves in >50weeks' postmenstrual age (PMA) in order to identify which infants are at risk for delayed resolution and to evaluate whether severe ROP developed after 50weeks' PMA. The medical records of infants screened for ROP from January 2008 to December 2016 at a tertiary care facility were reviewed retrospectively. Infants without follow-up prior to ROP resolution or complete retinal vascularization and those with retinal detachment were excluded. Delayed resolution of ROP was defined as presence of immature retinal vasculature at ≥50weeks' PMA. The birth characteristics, neonatal complications, and ROP characteristics of infants with and without delayed resolution were compared. A total of 996 infants were included, of whom 136 (13.6%) showed delayed resolution. Increasing severity of ROP (higher stage, lower zone, plus/pre-plus disease) and type 2 ROP was associated with delayed resolution (P<0.05). Other variables associated with delayed resolution included <28weeks gestational age, ≤3rd percentile birth weight, positive blood culture sepsis, necrotizing enterocolitis, intraventricular hemorrhage, and bronchopulmonary dysplasia (P<0.05). No infants developed type 1 after 50weeks' PMA. After a prolonged follow-up course consistent with AAP guidelines, a single patient in our study cohort was treated at 81weeks' PMA for persistent type 2 ROP. In our cohort, delayed resolution of ROP was more likely in infants with more severe ROP or a complex neonatal course. No patient with delayed resolution developed type 1 ROP after 50weeks' PMA, supporting AAP guidelines.

Peripheral retinal avascularity and capillary leakage in central serous chorioretinopathy

PurposeTo report a novel finding of peripheral retinal avascularity (PRA) and peripheral capillary leakage (PCL) on wide-field fluorescein angiography (WFA) in non-dependent quadrants, in eyes with bilateral chronic central serous chorioretinopathy (CSCR). MethodsForty six patients with bilateral CSCR were studied. Four patients had PRA and PCL, and 42 patients did not. The demographic profile, clinical findings, and imaging characteristics of the two groups were compared. ResultsThere was no significant difference between those patients with and without PRA and PCL with respect to the demographic profile, clinical findings, and imaging characteristics. Laser photocoagulation to extrafoveal points of leakage seen on fluorescein angiography (FA) was sufficient to cause complete resolution of CSCR in these 4 patients. PRA areas were not treated. ConclusionThe PRA and PCL in CSCR are novel findings, which have not been previously described.

Phenotypic analysis of Myo10 knockout (Myo10tm2/tm2) mice lacking full-length (motorized) but not brain-specific headless myosin X

We investigated the physiological functions of Myo10 (myosin X) using Myo10 reporter knockout (Myo10tm2) mice. Full-length (motorized) Myo10 protein was deleted, but the brain-specific headless (Hdl) isoform (Hdl-Myo10) was still expressed in homozygous mutants. In vitro, we confirmed that Hdl-Myo10 does not induce filopodia, but it strongly localized to the plasma membrane independent of the MyTH4-FERM domain. Filopodia-inducing Myo10 is implicated in axon guidance and mice lacking the Myo10 cargo protein DCC (deleted in colorectal cancer) have severe commissural defects, whereas MRI (magnetic resonance imaging) of isolated brains revealed intact commissures in Myo10tm2/tm2 mice. However, reminiscent of Waardenburg syndrome, a neural crest disorder, Myo10tm2/tm2 mice exhibited pigmentation defects (white belly spots) and simple syndactyly with high penetrance (>95%), and 24% of mutant embryos developed exencephalus, a neural tube closure defect. Furthermore, Myo10tm2/tm2 mice consistently displayed bilateral persistence of the hyaloid vasculature, revealed by MRI and retinal whole-mount preparations. In principle, impaired tissue clearance could contribute to persistence of hyaloid vasculature and syndactyly. However, Myo10-deficient macrophages exhibited no defects in the phagocytosis of apoptotic or IgG-opsonized cells. RNA sequence analysis showed that Myo10 was the most strongly expressed unconventional myosin in retinal vascular endothelial cells and expression levels increased 4-fold between P6 and P15, when vertical sprouting angiogenesis gives rise to deeper layers. Nevertheless, imaging of isolated adult mutant retinas did not reveal vascularization defects. In summary, Myo10 is important for both prenatal (neural tube closure and digit formation) and postnatal development (hyaloid regression, but not retinal vascularization).

Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis.

The mechanism underlying vasoproliferative retinopathies like retinopathy of prematurity (ROP) is hypoxia‐triggered neovascularisation. Nerve growth factor (NGF), a neurotrophin supporting survival and differentiation of neuronal cells may also regulate endothelial cell functions. Here we studied the role of NGF in pathological retinal angiogenesis in the course of the ROP mouse model. Topical application of NGF enhanced while intraocular injections of anti‐NGF neutralizing antibody reduced pathological retinal vascularization in mice subjected to the ROP model. The pro‐angiogenic effect of NGF in the retina was mediated by inhibition of retinal endothelial cell apoptosis. In vitro, NGF decreased the intrinsic (mitochondria‐dependent) apoptosis in hypoxia‐treated human retinal microvascular endothelial cells and preserved the mitochondrial membrane potential. The anti‐apoptotic effect of NGF was associated with increased BCL2 and reduced BAX, as well as with enhanced ERK and AKT phosphorylation, and was abolished by inhibition of the AKT pathway. Our findings reveal an anti‐apoptotic role of NGF in the hypoxic retinal endothelium, which is involved in promoting pathological retinal vascularization, thereby pointing to NGF as a potential target for proliferative retinopathies.

Fluorescein angiography of retinal vascular involution after intravitreal injection of ranibizumab for retinopathy of prematurity.

To describe the involution patterns of vessel growth of retina through fluorescein angiography (FA) of children, who had been under treatment up to 1y previously intravitreal ranibizumab (IVR) as monotherapy for retinopathy of prematurity (ROP). This is a retrospective study. The medical information and FA of 17 children (34 eyes) whose area of avascular retina from the ora serrata was more than two disc diameters (DD) were analyzed. Among 34 eyes, all were the presence of finger-shaped vessels and arteriolar-venular shunts (100%, 34/34 eyes). Popcorn abnormalities were found in most of the eyes (94.1%, 32/34 eyes). Furthermore, in many cases (23.5%, 8/34 eyes), there were leakage persisting in the region of the junction between avascular and vascular retina. In contrast, just 2 eyes (5.9%) showed damage of retinal capillary bed and 3 eyes (8.8%) showed large area of retinal pigment epithelium (RPE) atrophy. Although IVR can be very effective in ROP, we should remain cautious as infants may remain avascular peripheral retinas and abnormal vessel. FA allows accurate visualization of vessel abnormalities in eyes with ROP, which will be helpful to affect assessment of disease activity and therapeutic effect.