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Diabetic retinopathy neovascularization

Diabetic retinopathy neovascularization

Neovasculariization defining characteristic of PDR is the presence Anti-allergic home remedies new, Anti-allergic home remedies proliferating, blood reyinopathy. The status of the posterior vitreous is also significant in PDR evaluation as the presence of PVD is believed to be protective for the development of PDR [ 16171877 ]. Elbendary et al. Vascular wall von Willebrand factor in human diabetic retinopathy. Department of Mathematical Information Science, Asahikawa Medical University, Asahikawa, Japan. Diabetic retinopathy neovascularization

Diabetic retinopathy neovascularization -

Akihiro Ishibazawa ; Taiji Nagaoka ; Harumasa Yokota ; Atsushi Takahashi ; Tsuneaki Omae ; Young-Seok Song ; Tatsuhisa Takahashi ; Akitoshi Yoshida. Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan. Department of Mathematical Information Science, Asahikawa Medical University, Asahikawa, Japan.

Correspondence: Akihiro Ishibazawa, Department of Ophthalmology, Asahikawa Medical University, Midorigaoka Higashi , Asahikawa , Japan; bazawa14 asahikawa-med. Alerts User Alerts. Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography.

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Get Permissions. The hallmark of proliferative diabetic retinopathy PDR is neovascularization that occurs at the vitreoretinal interface. Neovascularization is often associated with tractional retinal detachment and vitreous hemorrhage, which are leading causes of visual loss in patients with diabetes.

In the landmark clinical trials of the Diabetic Retinopathy Study and Early Treatment Diabetic Retinopathy Study ETDRS , fluorescein angiography FA was used as an adjunct for classifying disease severity, evaluating the degree of macular edema, and guiding laser therapy.

However, FA is an invasive and time-consuming examination, and, therefore, it is not frequently performed. Optical coherence tomography OCT is a noninvasive technique that provides cross-sectional retinal imaging and has been used clinically to diagnose and follow structural changes, such as macular edema, in diabetic retinopathy.

Recently developed OCT angiography techniques are gaining popularity for use in three-dimensional noninvasive chorioretinal vascular imaging. This was shown in a study by Kuehlewein et al. Several authors have clearly shown neovascularization in PDR using en face OCT angiography.

This cross-sectional observational study was conducted at Asahikawa Medical University between December 1, , and March 8, The study was performed in adherence with the tenets of the Declaration of Helsinki and was approved by the institutional review board of the Asahikawa Medical University.

All subjects provided informed consent to participate in this research. Inclusion criteria involved new or previous diagnosis of PDR based on the International Clinical Diabetic Retinopathy and Diabetic Macula Edema Disease Severity Scales 26 and high-quality OCT angiograms of retinal neovascularization recorded during the study period.

High-quality OCT angiograms were defined by a signal strength of at least All patients underwent comprehensive ophthalmologic examination, including measurement of the best-corrected visual acuity BCVA , IOP, slit-lamp biomicroscopy, color fundus photography, and OCT.

Central macular thickness was measured using the ETDRS foveal central subfield by macular OCT. The following systemic clinical data were also recorded for all subjects at the time of ophthalmic examination: body mass index, blood pressure, hemoglobin A1c HbA1c level, and duration of diabetes.

Patients with any other retinal disorders, including history of vitreous surgery and the presence of media opacities, such as severe vitreous hemorrhage and cataract, were not included. Patients who previously received intravitreous injection of anti-VEGF drugs also were excluded. The classification of new vessels was based on location; NVD was defined as new vessels located at the disc or within 1 disc diameter from its margin, and NVE was defined as new vessels located outside this area.

Nineteen patients who were previously diagnosed with PDR received panretinal photocoagulation PRP. All patients were imaged using the commercially available spectral-domain OCT RTVue XR Avanti; Optovue, Fremont, CA, USA with AngioVue software Optovue to obtain en face OCT angiograms as previously described.

The instrument has an axial resolution of 5 μm and a lateral resolution of 15 μm with an imaging range of 2 to 3 mm in the tissue. Each OCT angiogram was created using orthogonal registration and by merging two consecutive scan volumes.

En face OCT angiograms 3 × 3 mm were obtained from adjacent regions of the posterior pole, including NVE, by moving the software scanning area without changing the fixation using the Angio Retina mode.

For assessment of NVD and NVE near the disc, OCT angiograms 3 × 3 mm or 4. We also confirmed the presence of new vessels using the B-scan OCT images with overlaying flow signal: the new vessels were observed as the structures with positive flow signal existing either on the retinal surface or protruding into the vitreous cavity.

To best visualize new vessels on each en face OCT angiogram, segmentation of the inner border on the B-scan was manually moved at the vitreous cavity above the new vessels, whereas that of the outer border was manually adjusted just below the internal limiting membrane ILM to minimize the depiction of superficial vascular plexus.

Morphologic and Quantitative Evaluation of New Vessels. On en face OCT angiograms, the structural characteristics of new vessels and vascular flow areas of NVD and NVE were evaluated.

The flow area was calculated by multiplying the number of pixels for which the decorrelation value was above that of the background with the pixel size, using the contained software RTVue, version Measurements of the flow area represented the average of values captured by two observers Y.

All data were expressed as the mean ± SD. The Mann-Whitney U test was used for statistical analysis of continuous variables, and the χ 2 test or Fisher's exact test was used for categorical variables. The Wilcoxon signed-rank test was used to compare flow areas before PRP with those after PRP in 12 eyes.

SPSS statistics software version A total of 40 eyes with PDR in 33 patients 22 males and 11 females were included in this study. The patients ranged in age from 32 to 74 years, with a mean age of Twenty eyes in 14 patients were treatment-naïve, and 20 eyes in 19 patients had been previously treated with PRP.

The demographic and clinical characteristics of treatment-naïve and previously treated patients are shown in the Table.

There were no significant differences in body mass index, blood pressure, HbA1c, and duration of diabetes between the groups. The intervals between PRP in treated eyes and study enrollment ranged from 6 months to 20 years.

Characteristic OCT Angiography Features of Retinal Neovascularization. In fundus biomicroscopy, new vessels were observed as irregular red blood columns on the optic nerve head and the retinal surface, or protruding into the vitreous cavity; however, their detailed structures were not seen clearly because of the background retinal structures and laser scars Figs.

On en face OCT angiograms, two distinct morphologic features of new vessels were identified. First, most new vessels had the lesions with irregular proliferation of fine vessels, which were defined as exuberant vascular proliferation EVP Fig. The second type of new vessels had pruned vascular loops of filamentous new vessels, but not EVP Fig.

Figure 1. View Original Download Slide. Optical coherence tomography angiography showing new vessel with two distinct morphologies. A Neovascularization at the disc in a year-old female with treatment-naïve PDR. Abnormal red blood columns can be observed on the optic nerve head white arrows , but their detailed morphology cannot be seen clearly.

B An OCT angiogram of the optic disc vividly shows the morphology of the NVD; that is, large-trunk vessels yellow arrows , terminal loops, and anastomotic connections at the outer border of neovascularization arrowheads.

The most distinguishing feature of this type of neovascularization is EVP, which can be identified as irregular proliferation of small-caliber new vessels ellipses. Scale bar : 0. C A horizontal B-scan image shows layer segmentation of the corresponding en face OCT angiogram shown on B.

D Another case of NVD in a year-old male with clinically inactive PDR treated with panretinal photocoagulation 1 year ago. New vessels near the nasal side of the disc can be seen faintly white-dot arrows , but their structures are not identified distinctly because of background retinal structures and laser scars.

E An OCT angiogram of the optic disc clearly shows the NVD has pruned vascular loops of filamentous new vessels arrows but does not have lesions of EVP. F A horizontal B-scan image shows layer segmentation of the corresponding en face OCT angiogram shown on E. Red and green lines in C and F are the inner and outer segmentation boundaries for en face OCT angiograms, respectively.

Figure 1 Optical coherence tomography angiography showing new vessel with two distinct morphologies. Relationship Between OCT Angiography Features and Fluorescein Leakage From Retinal Neovascularization in Treatment-Naïve or Previously Treated Eyes.

These new vessels were observed as whitish fibrovascular membranes by fundus examination. Four eyes in which FA could be performed had faint leakage from pruned new vessels without EVP during the early phase of FA Fig. Figure 2. Four representative cases with treatment-naïve proliferative diabetic retinopathy.

A — D Early-phase FA shows remarkable i. E — H Optical coherence tomography angiography images of 3 × 3 mm or 4. All treatment-naïve NVD and NVE cases have EVP ellipses , corresponding to the parts of active leakage in FA.

I — L Horizontal B-scan images show layer segmentation of the corresponding en face OCT angiograms shown on E to H , respectively. Red and green lines are the inner and outer boundaries, respectively.

Figure 2 Four representative cases with treatment-naïve proliferative diabetic retinopathy. Figure 3. Representative cases with treated, albeit still active, PDR. A An OCT angiogram 3 × 3 mm of NVE in the left eye of a year-old female.

The NVE has partial of EVP ellipse. B Early-phase FA of the same eye. Remarkable leakage from several NVEs is observed. The square outlines the area shown in A. C An OCT angiogram 3 × 3 mm of NVD in the right eye of a year-old male.

The NVD has pruned large-trunk vessels dotted arrows , saccular and dilated terminals, and anastomotic connection of outer borders. The NVD also exhibits EVP ellipses. D Early-phase FA of the same eye. Remarkable leakage from the NVD and several NVEs and preretinal hemorrhage are observed.

The square outlines the area shown in C. Figure 3 Representative cases with treated, albeit still active, PDR. Figure 4. Representative cases with treated inactive PDR. A A color fundus photograph of the left eye of a year-old male who received PRP 10 years ago.

The square outlines the area shown in B. B Optical coherence tomography angiography of a 4. There is no EVP. C Early-phase FA shows faint leakage from the NVD.

D A color fundus photograph of the left eye of a year-old female who received PRP 9 years ago. Whitish fibrovascular membrane is observed. The square outlines the area shown in E.

E Optical coherence tomography angiogram of the 3 × 3 mm area centered on the optic disc shows pruned NVD. There is also no EVP. F Early-phase FA shows faint leakage from the NVD.

Figure 4 Representative cases with treated inactive PDR. New vessels in all 36 eyes that were examined with FA showed leakage in the late phase approximately 5 minutes.

The sensitivity and specificity of detecting EVP on active leakage in early-phase FA were No significant differences in age, body mass index, blood pressure, HbA1c levels, duration of diabetes, BCVA, IOP, and central macular thickness were found between the eyes with EVP and those without EVP.

Changes in Retinal Neovascularization After Panretinal Photocoagulation. In eight treatment-naïve eyes and four previously treated eyes that still showed active new vessels, all of which had EVP, follow-up OCT angiograms were obtained 2 months after the start of PRP or after additional photocoagulation, respectively.

Morphologically, pruning of new vessels and reduction in EVP were observed after the treatment Figs. Additionally, the mean flow area of new vessels decreased significantly from 0.

Figure 5. A representative case of a year-old male with treatment-naïve PDR before and after PRP. A Early-phase FA before PRP shows remarkable leakage from NVD and numerous sites of NVE.

B Optical coherence tomography angiography in the 3 × 3 mm area centered on the optic disc clearly visualizes new vessels with lesions of EVP ellipse.

C Early-phase FA in the same eye 2 months after the start of PRP. Early leakage from NVD and NVEs are markedly diminished. The square outlines the area shown in D. D Optical coherence tomography angiography after PRP shows pruned NVD and decreased lesions of EVP. Figure 5 A representative case of a year-old male with treatment-naïve PDR before and after PRP.

Figure 6. Quantitative evaluation of the flow areas of NVE and NVD by OCT angiograms before and after photocoagulation. A , B Optical coherence tomography angiograms of treatment-naïve NVE in a year-old male. A Before PRP, the flow area of NVE was 1. Exuberant vascular proliferation of NVE is present.

B Two months after the start of PRP, the flow area is decreased to 0. The NVE has less EVP and becomes pruned. C , D Optical coherence tomography angiograms of a treatment-naïve NVD in a year-old man. C Before PRP, the flow area of NVD is 1. The NVD has remarkable EVP.

D Two months after the start of PRP, the flow area is decreased to 0. The NVD has less EVP and becomes pruned. The flow areas are decreased in all cases but one; the flow area in that case is conversely increased after PRP circumscribed plots. Figure 6 Quantitative evaluation of the flow areas of NVE and NVD by OCT angiograms before and after photocoagulation.

The time course of the treatment-naïve eye of a year-old female with NVD that had increased flow area following PRP is presented in Figures 7 and 8. At the first visit, FA showed no apparent signs of NVD Figs.

After 3 months, vascular sprouts developed into NVD with some evidence of EVP Fig. At that time, PRP treatment started developing in the inferior retina in a clockwise direction.

One month later, NVD exhibited signs of pruning, and the lesions associated with EVP were decreased Fig. Optical coherence tomography angiography performed at the end of 2 months of PRP showed that NVD had not disappeared, but had extended in a direction toward the macula Fig.

Montage OCT angiography of the optic disc and macula was created to examine the complete morphology of fibrovascular membrane, including new vessels 5 months after the start of PRP Fig.

The original NVD was now a large-trunk vessel, and new vessels were pruned; however, additional new vessels with EVP were extending toward the macula. Figure 7. The left eye of a year-old female with increased flow area of NVD after PRP shown on the graph in Figure 6. A A color fundus photograph at the first visit, the square outlines the area shown in the OCT angiograms below.

B Early-phase FA shows no apparent sign of NVD. C Optical coherence tomography angiography 3 × 3 mm reveals the presence of vascular sprout at the temporal rim of the disc yellow arrow. D Six weeks later, OCT angiography shows the growing sprout with the appearance of another new vessel sprout yellow circles.

E Three months after the first visit, the sprouts develop into an NVD with parts of EVP white ellipses. At this time, PRP treatment is started from the inferior retina in a clockwise direction. F , G Two weeks and 1 month later, respectively, the NVD becomes pruned and lesions with EVP are decreased white arrows.

H Two months later, PRP is completed, but OCT angiography 4. I , K Three and 4 months later, respectively, the NVD becomes pruned but grows and extends toward the macula white-dotted arrows. Figure 7 The left eye of a year-old female with increased flow area of NVD after PRP shown on the graph in Figure 6.

Figure 8. Images of the left eye of a year-old female shown in Figure 7 , 5 months after the start of PRP. A A color fundus photograph. White-dotted arrow indicates the location of horizontal line of OCT of B. B A horizontal OCT B-scan.

They were then deparaffinized, rehydrated, and subjected to immunohistochemistry. For an endothelial cell marker, rabbit anti-von Willebrand factor Dako, Glostrup, Denmark was used for labeling endothelial cells in blood vessels in adjacent sections.

An anti-α-smooth muscle actin ASMA monoclonal antibody directly conjugated to alkaline phosphatase Sigma, St.

Louis, MO was used in conjunction with the anti-tbdn-1 IgY antibody to double label sections of normal human eyes for simultaneous localization of tbdn-1 and pericytes. After a rinse in phosphate-buffered saline PBS , reactions were developed using the appropriate alkaline phosphatase—conjugated, species-specific secondary reagents anti-rabbit IgG, anti-mouse IgG, or anti-chicken IgY; Promega.

Red color reactions were generated using naphthol-AS-MX phosphate in the presence of fast red and levamisole to block endogenous tissue alkaline phosphatase activity.

In double-labeling experiments, the anti-tbdn-1 reaction was developed first using anti-IgY horseradish peroxidase and a diaminobenzidine DAB substrate kit Sigma to yield a dark brown color reaction for tbdn-1 expression, whereas the alkaline phosphatase anti-ASMA reaction was developed immediately after using fast red and levamisole, as stated above.

Slides were counterstained lightly using a 0. Sections were then rinsed, dried, and mounted Permount, Fisher, Pittsburgh, PA before viewing and photography using a microscope-mounted digital camera DC; Eastman Kodak, Rochester, NY.

Differences in immunohistochemical staining of tbdn-1 were quantitatively analyzed by measuring the total area of red chromogen in high-power fields of identical dimensions sampled from the retinal areas in normal and PDR specimens. Measurements were made using the magic wand and histogram command tools of an image-management program Photoshop; Adobe, Mountain View, CA run on a computer Macintosh G3; Apple Computer, Cupertino, CA , as described in a previously published method.

Cell lysates were prepared using Triton X lysis buffer 50 mM Tris [pH 8. Lysates were clarified by centrifugation, the protein concentration was quantified and samples analyzed by SDS-PAGE.

Western blot analysis was performed by standard procedures using chemiluminescence detection ECL Plus reagent; Amersham Pharmacia Biotech, Piscataway, NJ , except for low-salt buffer 25 mM NaCl conditions for Ab incubations and washes.

We first made a comparison of tbdn-1 expression in endothelial cell lines from different species. Western blot analysis indicated the presence of a 6-kDa tbdn-1 protein band in all these endothelial cell lines Fig.

As we have described previously, IEM cells display a kDa doublet that could correspond to acetylated and nonacetylated forms of tbdn Tbdn-1 Expression in Ocular Endothelial Homeostasis in Adults.

Tbdn-1 immunolocalization was performed in normal adult human eye specimens to determine the levels of tbdn-1 expression in normal adult ocular blood vessels. In four of four normal human adult eye specimens, both limbic Fig.

We also detected a very similar pattern of tbdn-1 expression in normal choroidal blood vessel endothelium see choroidal vessels stained in Fig.

The limbic and retinal blood vessels in normal adult human specimens showed the same staining pattern using an anti-von Willebrand factor antibody retinal vessels are shown in Figs. These results indicate that, in contrast to most vascular beds, tbdn-1 is expressed at high levels in endothelial linings of normal adult ocular blood vessels during homeostasis.

To assess whether tbdn-1 is expressed by retinal pericytes in vivo, we also analyzed normal human eye sections double stained for tbdn-1 and ASMA, a marker expressed by pericytes and perivascular contractile cells and not by endothelial cells.

Figure 3 shows a representative view of a normal human retinal blood vessel double stained for tbdn-1 Fig. The tbdn-1 and ASMA stains did not colocalize in retinal blood vessels in normal human eye sections. These results indicate that tbdn-1 does not appear to be expressed in retinal pericytes at the same high levels at which it is expressed in retinal endothelial cells in vivo.

Suppression of Tbdn-1 Expression during Capillary Formation of a Choroid-Retina Endothelial Cell Line. Our previous work has shown that tbdn-1 protein expression is downregulated during capillary formation of the IEM embryonic vascular endothelial cell line in vitro. These capillary colonies can then be fixed, embedded, and histologically sectioned for immunocytochemical studies as we have previously described for IEM capillary colonies.

Suppression of Tbdn-1 Expression during Retinal Neovascularization in PDR. Tbdn-1 immunolocalization was performed in diabetic adult human eye specimens in parallel with the normal samples to determine whether the expression characteristics of tbdn-1 in retinal blood vessels change during PDR.

Sections of five of five eyes from patients with PDR that were processed and stained simultaneously with the normal human eye samples showed a dramatically lower level of expression of endothelial tbdn-1 protein in the diseased areas of the retinas showing neovascularization. Tbdn-1 was suppressed or completely absent from abnormal proliferating blood vessels and fronds in both preretinal membranes and neural retinal areas in the PDR specimens Fig.

PDR specimens showed no change in tbdn-1 levels in the limbic vessels in the anterior portion of the eye in the same sections compare Fig. Thus, the suppression of tbdn-1 expression occurred in blood vessels within the neural retina and preretinal membranes but did not occur in limbic vessels in the anterior portions of the same PDR specimens.

The limbic vessel expression of tbdn-1 in PDR also served as an internal positive control for tbdn-1 expression in these specimens. We also observed that tbdn-1 was downregulated in the choroidal vessels in the PDR specimens in comparison to choroidal vessels in normal specimens Fig.

Expression of the endothelial marker von Willebrand factor was detected at high levels, similar to normal retinal blood vessels, in blood vessels showing decreased tbdn-1 expression from the same PDR specimens Fig.

These results indicate that tbdn-1 expression is suppressed in abnormal proliferating blood vessels of the neural retina and preretinal membranes in PDR. Tbdn-1 expression peaks during early to middle stages of development of most blood vessels and is downregulated at later stages of maturation, suggesting it may be involved with regulating specific stages of blood vessel maturation during embryogenesis.

These studies suggest that tbdn-1 may play a role in some specialized vascular beds during adulthood as well. The results of the present study provides two lines of evidence to suggest that tbdn-1 expression may be involved in maintaining ocular blood vessel homeostasis. First, tbdn-1 expression persisted at high levels in normal adult ocular blood vessels.

Second, retinal endothelial tbdn-1 expression was suppressed in neovascularization of PDR. In interpreting these data, it could be argued that the observed loss of tbdn-1 was due simply to loss of endothelial cells or, alternatively, to loss of pericytes, if it were the case that tbdn-1 was also expressed by retinal pericytes.

Our present results and the results of others 19 have shown that diseased blood vessels in PDR specimens retain expression of the endothelial marker von Willebrand factor, indicating that the decrease in tbdn-1 expression is not merely a consequence of loss of all vascular endothelial cells in these blood vessels, as has been reported for some vascular beds in certain stages of retinopathy in other studies.

Furthermore, to assess whether tbdn-1 could be expressed by pericytes in vivo, we analyzed human eye sections double stained for tbdn-1 and ASMA, a cytoskeletal isoform of vascular actin expressed by pericytes and nonendothelial perivascular contractile cells.

Our results do not exclude the possibility that tbdn-1 may be expressed in pericytes at very low levels below the limit of detection by these methods. Nevertheless, all these results taken together indicate that suppression of retinal blood vessel tbdn-1 expression in neovascularization of PDR is a reflection of a decrease in tbdn-1 levels in retinal endothelial cells rather than a reflection of cell loss.

Because tbdn-1 is expressed in normal retinal endothelium but is suppressed in retinal endothelium of PDR, our results prompt speculation that a possible functional role for tbdn-1 in normal retinal capillaries may be to participate in a mechanism that may dampen capillary outgrowth.

Conversely, because tbdn-1 suppression is associated with the abnormal retinal capillary outgrowth occurring during neovascularization in PDR, removal of such a potential dampening influence of tbdn-1 may permit outgrowth of retinal capillaries in the diabetic environment.

Although retinal and choroidal capillaries are anatomically and physiologically different, choroidal pathologic neovascularization occurs in PDR.

Our results suggest that the microenvironment in the disease-affected regions in PDR retinas may harbor a local milieu that supports the downregulation of tbdn-1, in that limbic vascular tbdn-1 levels were not different from normal in the PDR specimens we analyzed see the Results section and Fig.

This hypothesis is also supported by our observation that both blood vessels and capillary fronds showed a suppression of tbdn-1 expression in the tissues of PDR-affected retinas. The PDR microenvironment may include factors present in PDR retinal tissue that may lead to downregulation of tbdn-1 levels.

Furthermore, the abnormal death of cells such as pericytes in the retinal vascular wall may cause derangements in the diabetic retinal microenvironment to which the remaining and viable retinal endothelial cells become exposed.

A range of angiogenic growth factors VEGF, bFGF, and IGF-1 , integrins, and derangements of extracellular matrix ECM components such as collagen type IV are associated with pathologic neovascularization in PDR, any or all of which could potentially affect tbdn-1 expression. and is known to contain a range of ECM components, such as collagen type IV, heparan sulfate proteoglycans, laminin, and entactin.

Despite the likely caveats associated with interpreting the regulation of endothelial behavior in reconstitution experiments in vitro and during PDR in vivo, our results indicate a correlation between suppression of tbdn-1 expression and retinal capillary formation occurring in choroid-retina capillary outgrowth in vitro and during neovascularization of PDR in vivo.

We are currently in the process of identifying the ECM components that may regulate tbdn-1 expression. Of particular interest, the expression of tbdn-1 in normal adult retinal blood vessels parallels the expression of pigment epithelium derived factor PEDF in adult retina, a recently described novel antiangiogenic serpin family member produced by the normal retinal pigment epithelium.

Decreases in the expression levels of PEDF have been observed during oxygen-induced retinal neovascularization in mice and rats, 30 31 and systemic administration of PEDF to mice with ischemia-induced retinopathy prevents retinal neovascularization in this model.

We also do not know at this time whether tbdn-1 can be regulated either directly or indirectly by PEDF. Although animal models of retinal neovascularization have been studied, little information is available about the intracellular mechanisms in retinal vascular cells that are associated with neovascularization during PDR in human specimens.

Polymorphisms of the aldose reductase gene, which may alter aldose reductase mRNA levels within cells, are thought to predispose patients with diabetes to retinopathy through possible disturbances in the polyol pathway and subsequent vascular damage. Our finding of high levels of tbdn-1 expression in adult ocular blood vessel endothelial cells during homeostasis and the loss of this expression of tbdn-1 during retinal capillary outgrowth occurring in PDR sheds light on the intracellular processes that are disregulated during neovascularization associated with PDR.

The re-expression of tbdn-1 in diseased vessels in PDR may be necessary to restore homeostasis and stop neovascularization. Tbdn-1 is associated with an acetyltransferase activity and contains protein—protein interaction and DNA binding-like motifs.

Submitted for publication January 17, ; revised July 17, ; accepted August 6, Commercial relationships policy: N. The publication costs of this article were defrayed in part by page charge payment. Corresponding author: Robert L. rlgendron chmcc.

F igure 1. View Original Download Slide. Tbdn-1 was specifically detected by anti-tbdn-1 Ab antibody in mouse and human vascular endothelial cells and in rhesus macaque choroid-retina endothelial cells. Arrow : kDa tbdn-1 band, which resolves as a doublet in the IEM cells.

F igure 2. Tbdn-1 protein and endothelial marker expression in sections of normal adult human eye. A Limbic vessel tbdn-1 expression red stain; arrows : tbdn-1—positive endothelial cells in a limbic blood vessel.

C , E Retinal endothelial tbdn-1 expression in longitudinal- and transverse-sectioned blood vessels in normal adult eye red stain; arrows: tbdn-1—positive endothelial cells in retinal blood vessels.

B , D Retinal endothelial von Willebrand factor expression in longitudinal- and transverse-sectioned blood vessels in normal adult eye red stain, arrows : von Willebrand factor—positive endothelial cells in retinal blood vessels.

Adjacent sections stained with equal concentrations of preimmune IgY control antibody showed no staining F. G A low-power and labeled view of a methyl green—stained section of the retinal areas shown in A — F is provided for orientation purposes.

Sections were developed using alkaline phosphatase and fast red substrate; methyl green counterstain. lmb, limbic region of cornea; nr, neural retina; vb, vitreous body; cbrc, cell bodies of rods and cones; opl, outer plexiform layer; ibpcl, integrating bipolar cell layer; ipl, inner plexiform layer; gcl, ganglion cell layer.

Scale bar, 50μ m. F igure 3. Double staining for tbdn-1 and ASMA in a retinal vessel of a normal human eye section. Shown is a representative view of a normal human retinal blood vessel double stained for tbdn-1 dark brown peroxidase stain and ASMA bright red alkaline phosphatase stain.

The tbdn-1 and ASMA stains did not colocalize in these retinal blood vessels in normal human eye sections. Black arrows : locations of tbdn-1 expression brown staining in endothelial cells; white arrows : locations of ASMA expression bright red staining in pericyte and perivascular contractile cells.

F igure 4. B , arrows Similar capillary sprouts as indicated by arrows in A ; cl indicates main body of the colony. Staining of sections was developed using alkaline phosphatase and fast red substrate. Methyl green counterstain in B reveals the capillary sprouts shown by arrows in the capillary colony before processing, in A , and after processing, in B.

F igure 5. Tbdn-1 protein expression was suppressed in specimens of eyes from patients with PDR. A Retinal endothelial tbdn-1 expression arrows : retinal blood vessels stained red in normal adult eye. C — E Tbdn-1 staining in blood vessels in preretinal membranes in sections of eyes from three separate representative patients with PDR.

F Tbdn-1 staining in blood vessel fronds cut longitudinally in a neural retinal area in a section of eye from a fourth and separate representative patient. C , F , insets von Willebrand factor staining of abnormal blood vessels arrows in sections from the same PDR specimens and adjacent to those stained for tbdn Blood vessels in the diseased retinal tissue showed either very low levels of tbdn-1 expression or no detectable tbdn-1 expression, compared with normal specimens, whereas the same abnormal blood vessels expressed von Willebrand factor see also the Results section for quantitative analysis of tbdn-1 expression levels in these sections.

B Tbdn-1 staining arrow , red of limbic blood vessels in the anterior part of the same section as that shown in D to exemplify normal tbdn-1 expression in unaffected areas of PDR-affected eyes.

All sections were also incubated with equal concentrations of preimmune IgY and showed no staining see example in Fig. Low-power views of a normal retina G and a diabetic retina with a preretinal membrane H , both stained for tbdn-1 are provided for orientation purposes. Sections were developed using alkaline phosphatase and fast red substrate with methyl green counterstain.

lmb, limbic region of cornea; nr, neural retina; vb, vitreous body; c, choriocapillaris; preretinal membrane.

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Akihiro Achieving refreshed and youthful skin Diabeetic, Taiji NagaokaHarumasa Yokota retjnopathy, Atsushi Diabetic retinopathy neovascularizationTsuneaki OmaeNeovascualrization SongTatsuhisa Takahashi nelvascularization, Akitoshi Diabetic retinopathy neovascularization Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Neovzscularization Coherence Natural stress relief remedies Angiography. Purpose : To characterize the morphology of neovascularization at the disc NVD and neovascularization elsewhere NVE in treatment-naïve or previously treated proliferative diabetic retinopathy PDR patients using optical coherence tomography OCT angiography. Results : Twenty eyes had treatment-naïve PDR, whereas 20 eyes were previously treated with PRP. Conclusions : Exuberant vascular proliferation on OCT angiograms should be considered as an active sign of neovascularization; therefore, morphologic evaluation of neovascularization using OCT angiography may be useful to estimate the activity of each neovascularization in eyes with PDR. Purchase this article with an account. Jump To Dlabetic and proliferated blood vessels at retinopathhy level of the retinal ganglion cell layer. Fibrin thrombus Achieving refreshed and youthful skin retinlpathy present in the vessel on the right hematoxylin-eosin. Endothelial cells in a proliferation of vessels are highlighted using antibodies to CD34 anti-CD34 immunostain. Proia ADCaldwell MC. Intraretinal Neovascularization in Diabetic Retinopathy.

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STOP Diabetic Retinopathy: Skills Training in Ophthalmic Photocoagulation

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