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Biomedical subjects

Atsushi Otani

Publications and source records attributed to Atsushi Otani.

17 recordsLinked to original sources
PubMed2006

Pigment epithelial detachment in polypoidal choroidal vasculopathy.

PURPOSE: To study the morphological features of serosanguineous pigment epithelial detachments (PEDs) with accompanying polypoidal lesions in eyes with polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective observational case series. METHODS: For this observational case study, we retrospectively reviewed 93 consecutive eyes of 85 patients with PCV. The lesions in eyes with PCV were examined with indocyanine green angiography (IA) and optical coherence tomography (OCT). RESULTS: Of 93 eyes with PCV, 51 eyes (55%) had serous or hemorrhagic PEDs. Of these 51 eyes, a notch in the PED was found in 27 eyes (53%) by angiography, most of which showed polypoidal lesions by IA that corresponded in location to the notch observed by angiography. Polypoidal lesions were detected outside the PED in one eye (2%), at the margin of the PED in 33 eyes (65%), and inside the PED in 12 eyes (24%). OCT revealed that PED had a notch observed tomographically in 29 eyes (57%), most of which corresponded in location to polypoidal lesions seen by IA. In eight eyes, polypoidal lesions, which were adherent to the inner surface of the serous PED, appeared to be detached from the Bruch membrane and the choroid. CONCLUSIONS: Polypoidal lesions are located at the margin of PED and make a notch in the accompanying PED that is visible by angiography and tomographically. When the polypoidal lesions have increased exudate, the fluid from the lesions infiltrates under the polypoidal lesions themselves, which results in the lesions detaching from the Bruch membrane and appearing to be located inside the PED.

Aged↗
PubMed2006

No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese.

Age-related macular degeneration (ARMD) is the leading cause of blindness in the elderly population not only Western but also Asian industrial countries. In Caucasian, a polymorphism of the complement factor H gene (CFH), the C allele of rs1061170 (Y402H), was established as the first strong genetic factor for excursively exudative type of ARMD. In this study, we performed an extensive sequencing of the 22 exons in the CFH gene by recruiting 146 exudative ARMD patients and 105 normal controls of Japanese origin and identified 61 polymorphisms. We found that the frequency of the C allele of rs1061170 (Y402H) is much lower (0.04) in Japanese controls than in Caucasians (0.45). No case disease susceptibility to exudative ARMD was noted for rs1061170 (Y402H) (chi (2) = 3.19, P (corr) = 0.423), or other 12 single nucleotide polymorphisms (SNPs) whose frequency is greater than 0.05. When haplotypes were inferred for 13 SNPs (these 12 SNPs with a frequency greater than 0.05 and rs1061170), three haplotypes whose pattern was similar to those in Caucasians were identified but with substantial difference in frequency. Again we failed to identify genetic association between Japanese exudative ARMD and any of the haplotypes including the J1 haplotype which was shown to be susceptible to ARMD in Caucasians (chi (2 )=( )3.92, P (corr) = 0.157). CFH does not appear to be a primary hereditary contributor to ARMD in Japanese. The absence of CFH contribution to ARMD in Japanese may correlate with the findings in ethnic differences of ARMD phenotypes.

Age Factors↗
PubMed2006

Recurrent bleeding after photodynamic therapy in polypoidal choroidal vasculopathy.

PURPOSE: To report a case of recurrent bleeding after photodynamic therapy (PDT) in an eye with polypoidal choroidal vasculopathy (PCV). DESIGN: Interventional case report. METHODS: A 73-year-old man was treated in the left eye for PCV with PDT. RESULTS: Two weeks after PDT, his left eye showed extensive subretinal hemorrhage, with a slight vision loss. Three months after PDT, subretinal hemorrhage was almost absorbed. He received a second session of PDT to the remaining choroidal neovascularization. Two weeks thereafter, his left eye showed massive suprachoroidal hemorrhage with further vision loss. One month after the second PDT, visual acuity was decreased to no light perception as a result of massive vitreous hemorrhage. Although the patient underwent pars plana vitrectomy, visual acuity in the left eye remained hand motion as a result of massive suprachoroidal hemorrhage. CONCLUSIONS: Ophthalmologists and patients should be aware of the risk of massive bleeding after PDT in eyes with PCV.

Aged↗
PubMed2006

Polypoidal choroidal vasculopathy with choroidal vascular hyperpermeability.

PURPOSE: To describe the incidence and clinical characteristics of polypoidal choroidal vasculopathy (PCV) associated with choroidal vascular hyperpermeability. DESIGN: Retrospective observational case series. METHODS: We reviewed the medical records of 122 consecutive eyes with PCV and 106 consecutive eyes with exudative age-related macular degeneration (AMD). Fluorescein angiography and indocyanine green (ICG) angiography were performed using a confocal scanning laser system. In the midphase of ICG angiography, we evaluated choroidal vascular hyperpermeability, which is recognized as one of the characteristic findings in central serous chorioretinopathy (CSC). Choroidal vascular hyperpermeability appeared as multifocal patchy areas of hyperfluorescence with blurred margins within the choroid that increased in intensity with time after injection of the dye. RESULTS: Of 122 eyes with PCV, 12 (9.8%) eyes of 10 patients exhibited multifocal choroidal hyperfluorescence in the midphase of ICG angiography, whereas two (1.9%) of 106 eyes with exudative AMD showed a similar appearance (P = .013). Of the 12 eyes in 10 patients with PCV that demonstrated multifocal choroidal hyperfluorescence, we also noted that the early phase of ICG angiography showed choroidal filling delay in seven eyes (58%) and venous dilation in 12 eyes (100%). Four of these 12 eyes (33%) had a medical history of CSC, and nine (90%) of the 10 patients revealed multifocal choroidal hyperfluorescence bilaterally. CONCLUSIONS: Multifocal choroidal hyperfluorescence seen by ICG angiography occurs more frequently in eyes with PCV than in those with AMD. Choroidal vascular hyperpermeability, reportedly a characteristic finding in CSC, might be one of the risk factors of PCV.

Aged↗
PubMed2004

Adult bone marrow-derived stem cells use R-cadherin to target sites of neovascularization in the developing retina.

Adult bone marrow contains a population of hematopoietic stem cells (HSCs) that can give rise to cells capable of targeting sites of neovascularization in the peripheral or retinal vasculature. However, relatively little is known about the mechanism of targeting of these cells to sites of neovascularization. We have analyzed subpopulations of HSCs for the expression of a variety of cell surface adhesion molecules and found that R-cadherin, a calcium-dependent cell-cell adhesion molecule important for normal retinal endothelial cell guidance, was preferentially expressed by functionally targeting HSCs. Preincubation of HSCs with function-blocking anti-R-cadherin antibodies or novel R-cadherin-specific peptide antagonists effectively prevented targeting of bone marrow-derived cells to the developing retinal vasculature in vivo. Whereas control-injected HSCs targeted to all 3 normal developing retinal vascular layers, blocking R-cadherin-mediated adhesion resulted in mistargeting of the HSCs to the normally avascular outer retina. Our results suggest that vascular targeting of bone marrow-derived HSCs is dependent on mechanisms similar to those used by endogenous retinal vascular endothelial cells. Thus, R-cadherin antagonists may be useful in the treatment of neovascular diseases in which circulating HSCs contribute to abnormal angiogenesis.

Animals↗
PubMed2004

Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells.

Inherited retinal degenerations afflict 1 in 3,500 individuals and are a heterogeneous group of diseases that result in profound vision loss, usually the result of retinal neuronal apoptosis. Atrophic changes in the retinal vasculature are also observed in many of these degenerations. While it is thought that this atrophy is secondary to diminished metabolic demand in the face of retinal degeneration, the precise relationship between the retinal neuronal and vascular degeneration is not clear. In this study we demonstrate that whenever a fraction of mouse or human adult bone marrow-derived stem cells (lineage-negative hematopoietic stem cells [Lin- HSCs]) containing endothelial precursors stabilizes and rescues retinal blood vessels that would ordinarily completely degenerate, a dramatic neurotrophic rescue effect is also observed. Retinal nuclear layers are preserved in 2 mouse models of retinal degeneration, rd1 and rd10, and detectable, albeit severely abnormal, electroretinogram recordings are observed in rescued mice at times when they are never observed in control-treated or untreated eyes. The normal mouse retina consists predominantly of rods, but the rescued cells after treatment with Lin- HSCs are nearly all cones. Microarray analysis of rescued retinas demonstrates significant upregulation of many antiapoptotic genes, including small heat shock proteins and transcription factors. These results suggest a new paradigm for thinking about the relationship between vasculature and associated retinal neuronal tissue as well as a potential treatment for delaying the progression of vision loss associated with retinal degeneration regardless of the underlying genetic defect.

Adult↗
PubMed2003

Potential role of the angiopoietin/tie2 system in ischemia-induced retinal neovascularization.

PURPOSE: Ischemia-induced neovascularization can cause catastrophic loss of vision in retinal disorders such as diabetic retinopathy. Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and is involved in pathologic angiogenesis. In the study described herein, the role of these molecules in ischemic retinal disorders was investigated. METHODS: Human epiretinal membranes were examined by immunohistochemistry, In situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Effects of angiopoietins on tube formation were studied in vitro in bovine retinal capillary endothelial cells (BRECs) and in a murine model of ischemia-induced retinal neovascularization. RESULTS: In human epiretinal membranes surgically obtained from eyes with ischemic retinal disorders, substantial upregulation of angiopoietin 2 (Ang2) and the receptor Tie2 was recorded than in those from eyes with nonischemic diseases, whereas expression of Ang1 was constant in all membranes. Both Ang1 and Ang2 promoted tube-forming activity and enhanced the effects of vascular endothelial growth factor (VEGF) in cultured BRECs. Soluble Tie2 fusion protein (sTie2-Fc), which precluded modulation of VEGF-dependent tube formation by the angiopoietins, suppressed both VEGF and hypoxia-conditioned, medium-induced tube-forming activity in BRECs. Intravitreal injection of sTie2-Fc, soluble Flt-1 fusion protein (sFlt-1-Fc), and both chimeric proteins suppressed retinal angiogenesis in a murine model of retinal ischemia in the order of sTie2-Fc < sFlt-1-Fc < sTie2-Fc+sFlt-1-Fc. CONCLUSIONS: These results reinforce the substantial role of the angiopoietins/Tie2 system in ischemia-induced angiogenesis as well as the VEGF system and suggest that combined inhibition of Tie2 and VEGF signaling may be more effective in halting or preventing pathologic angiogenesis in ischemic retinal disorders.

Adult↗
PubMed2002

Bone marrow-derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis.

Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin(+)) or non-hematopoietic (Lin(-)) lineages. Lin(-) hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin(-) BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin(-) BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin(-) BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin(-) HSC may be a useful therapeutic approach for the treatment of many ocular diseases.

Animals↗
PubMed2002

A fragment of human TrpRS as a potent antagonist of ocular angiogenesis.

Pathological angiogenesis contributes directly to profound loss of vision associated with many diseases of the eye. Recent work suggests that human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) link protein synthesis to signal transduction pathways including angiogenesis. In this study, we show that a recombinant form of a COOH-terminal fragment of TrpRS is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in a mouse model and of naturally occurring retinal angiogenesis in the neonatal mouse. The angiostatic activity is dose-dependent in both systems. The recombinant fragment is similar in size to one generated naturally by alternative splicing and can be produced by proteolysis of the full-length protein. In contrast, the full-length protein is inactive as an antagonist of angiogenesis. These results suggest that fragments of TrpRS, as naturally occurring and potentially nonimmunogenic anti-angiogenics, can be used for the treatment of neovascular eye diseases.

Alternative Splicing↗
PubMed2002

A human aminoacyl-tRNA synthetase as a regulator of angiogenesis.

Aminoacyl-tRNA synthetases catalyze the first step of protein synthesis. It was shown recently that human tyrosyl-tRNA synthetase (TyrRS) can be split into two fragments having distinct cytokine activities, thereby linking protein synthesis to cytokine signaling pathways. Tryptophanyl-tRNA synthetase (TrpRS) is a close homologue of TyrRS. A natural fragment, herein designated as mini TrpRS, was shown by others to be produced by alternative splicing. Production of this fragment is reported to be stimulated by IFN-gamma, a cytokine that also stimulates production of angiostatic factors. Mini TrpRS is shown here to be angiostatic in a mammalian cell culture system, the chicken embryo, and two independent angiogenesis assays in the mouse. The full-length enzyme is inactive in the same assays. Thus, protein synthesis may be linked to the regulation of angiogenesis by a natural fragment of TrpRS.

Animals↗
PubMed2002

Inhibitory mechanism of vascular endothelial growth factor (VEGF) by bucillamine.

1. Vascular endothelial growth factor (VEGF) plays an important role in the neovascularization of ischaemic retinal diseases such as proliferative diabetic retinopathy. We determined that bucillamine, an anti-rheumatic drug, inhibits the VEGF production induced by hypoxia in bovine retinal microcapillary endothelial cells (BREC). To further clarify the inhibitory mechanism, we investigated the possible mechanism by which bucillamine exerts this inhibitory effect. 2. Bucillamine (100 micro M) decreased the hypoxia-induced increase of VEGF mRNA by 54.5% (P<0.001). Bucillamine (100 micro M) reduced the hypoxia-induced VEGF content in culture media by 29.0% (P<0.001), while monosulfydryl drugs, N-acetylcysteine and D-penicillamine, did not. 3. Bucillamine (100 micro M) did not affect VEGF mRNA half-life (hypoxia, 4.3 h; hypoxia+bucillamine, 3.9 h; normoxia, 2.7 h; normoxia+bucillamine, 2.7 h). 4. Reporter gene studies revealed that bucillamine reduced transcriptional activity in the 5'-flanking region of the VEGF gene by 74.0%. Hypoxia stimulated binding activity of BREC nuclear protein to a hypoxia responsive element (HRE), which was decreased by bucillamine. 5. Bucillamine inhibited hypoxic-induction of HIF-1alpha mRNA by 73.1% (P<0.001). Bucillamine also inhibited spontaneous VEGF mRNA expression by 26.6%. Furthermore, it inhibited activity of VEGF promoter and decreased binding activity to Sp1 and HRE, but did not alter AP1 and AP2 activity in normoxia. 6. These data suggest that bucillamine inhibits hypoxic induction of VEGF through inhibition of HIF-1 induction and binding activity in BREC. Bucillamine also inhibits the spontaneous expression of VEGF mRNA by its effect on Sp1 and HRE binding.

Animals↗
PubMed2002

Contrasting effect of estrogen on VEGF induction under different oxygen status and its role in murine ROP.

PURPOSE: It has been reported that 17beta-estradiol (E2) may enhance the proliferation of bovine retinal vascular endothelial cells (BRECs) by increasing the expression of VEGFR-2 and VEGF. The hypothesis in the current study was that estrogen may contribute to fetal vascular development and the cessation of exposure to estrogen of premature infants on birth may have an inhibitory effect on retinopathy of prematurity (ROP). Because ROP is thought to develop under relative hypoxia after exposure to high-dose oxygen, this study was conducted to investigate how estrogen modulates hypoxia-induced VEGF in BRECs and mouse ROP. METHODS: Gene expression of VEGF and hypoxia-inducible factor (HIF)-1alpha were studied in BRECs, with or without E2, under normoxia and hypoxia (1% O2). A binding assay was performed to determine whether estrogen interferes with HIF-1-mediated induction of VEGF. In a mouse ROP model, effects of E2 were evaluated by avascular area, subsequent extraretinal neovascularization, and retinal expression of the VEGF gene, by administering E2 during hyperoxia (75% O2) and/or after exposure to room air. RESULTS: Hypoxia-induced VEGF mRNA in BRECs was reduced dose dependently by 1 to 100 nM E2. E2 reduced hypoxia-induced binding of HIF-1 to the VEGF promoter site and reduced the HIF-1alpha mRNA level. In mouse ROP, injection of E2 during hyperoxia increased retinal VEGF mRNA and reduced the retinal avascular area at the end of hyperoxia. E2 treatment during the normoxia that followed reduced VEGF mRNA and extraretinal neovascularization. Treatment with E2 throughout both periods significantly improved retinopathy. CONCLUSIONS: Estrogen may function as a significant modulator of the level of VEGF mRNA under different oxygen conditions and could serve as a prophylactic agent for ROP.

Animals↗
PubMed2001

Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis.

Neuropilin (NRP) 1, previously identified as a neuronal receptor that mediates repulsive growth cone guidance, has been shown recently to function also in endothelial cells as an isoform-specific receptor for vascular endothelial growth factor (VEGF)(165) and as a coreceptor in vitro of VEGF receptor 2. However, its potential role in pathologic angiogenesis remains unknown. In the present study, we first show that VEGF selectively up-regulates NRP1 but not NRP2 via the VEGF receptor 2-dependent pathway. By NRP1 binding analysis, we showed that its induction by VEGF accompanies functional receptor expression. Endothelial proliferation stimulated by VEGF(165) was inhibited significantly by antibody perturbation of NRP1. In a murine model of VEGF-dependent angioproliferative retinopathy, intense NRP1 mRNA expression was observed in the newly formed vessels. Furthermore, selective NRP1 inhibition in this model suppressed neovascular formation substantially. These results suggest that VEGF cannot only activate endothelial cells directly but also can contribute to robust angiogenesis in vivo by a mechanism that involves up-regulation of its cognate receptor expression.

Animals↗
PubMedDate not supplied

Role of vitronectin receptor-type integrins and osteopontin in ischemia-induced retinal neovascularization.

PURPOSE: It has been reported that vitronectin receptor-type integrins mediate vascular cell proliferation and migration. In this study, we investigated the expression of vitronectin receptor-type integrins and osteopontin in ischemia-induced retinal neovascularization, and examined the role of osteopontin in angiogenesis as a ligand of vitronectin receptor-type integrins. METHODS: Retinal neovascularization was produced by exposing C57BL/6J mice to 75% oxygen from postnatal day (P) 7 to P12. Expression of vitronectin receptor-type integrins and osteopontin was assessed by Northern blot analysis, in situ hybridization, and immunofluorescence. The role of osteopontin in retinal angiogenesis was evaluated by tube formation assay using cultured bovine retinal microcapillary endothelial cells. RESULTS: In the murine model, integrin alpha(v) mRNA was increased from P14 with a 2.6-fold peak response observed on P19, when retinal neovascularization was remarkable. Indirect immunofluorescence for vitronectin receptor-type integrins revealed prominent expression of integrin alpha(v)beta3/beta5 in the neovascular endothelial cells. Osteopontin mRNA was increased from P14, with a 2.0-fold peak response observed on P19. In situ hybridization demonstrated localization of osteopontin mRNA in neovascular tufts. Vascular endothelial growth factor-induced tube formation (8.3 +/- 0.6 mm/field) was inhibited significantly by treatment with anti-osteopontin antibody (4.8 +/- 0.7 mm/field, P <.001). CONCLUSIONS: These data suggest that increased expression of both vitronectin receptor-type integrins and osteopontin in ischemic retina contribute to vascular endothelial cell proliferation and to retinal vascular formation by promoting interaction between endothelial cells and extracellular matrix, which leads to retinal neovascularization.

Animals↗
PubMedDate not supplied

Retinal vascular regeneration.

We discuss the potential use of stem cells for therapeutic angiogenesis in the treatment of retinal diseases. We demonstrate that the clinical utility of these EPC may be not limited in the treatment of ischemic retinal diseases but may also have application for the treatment of retinal degenerative disorders and for a form of cell-based gene therapy. One of the greatest potential benefits of bone marrow derived EPC therapy is the possible use of autologous grafts. Nonetheless, potential toxicities and unregulated cell growth will need to be carefully evaluated before this approach is brought to the clinics.

Animals↗