Macrophage Integrin-Mediated, HuR-Dependent Angiogenic Factor Gene Expression

Activated macrophages, via the secretion of pro-angiogenic factors, modulate the angiogenic response to inflammation. Several of these factors, including vascular endothelial growth factor (VEGF), are encoded by inherently unstable mRNA transcripts containing AU-rich elements (AREs) in their 3\u27 untranslated region. During stress events, the half-lives of these mRNAs must be prolonged to allow for significant protein production and an adequate angiogenic response. This laboratory has demonstrated that engagement of the β-integrin receptor, LFA-1, leads to stabilization of ARE-bearing mRNAs in T lymphocytes through a nuclear-to-cytoplasmic translocation of the RNA-binding protein, HuR. Here, we address whether β-integrin engagement stabilizes VEGF mRNA in macrophages in vitro and at sites of angiogenesis via a HuR-dependent mechanism. To determine whether β-integrin engagement regulates VEGF mRNA stability, we adhered primary mouse bone marrow-derived macrophages to ICAM-1 β-integrin ligand) for 3 hours. VEGF mRNA degradation was measured by quantitative RT-PCR after transcriptional inhibition. In the cells bound to ICAM-1, the VEGF mRNA remained stable, whereas, in non-integrin engaged control cells, VEGF mRNA degraded to less than 50% of initial levels within 60 minutes. Furthermore, in BMDMs deficient in HuR expression, VEGF mRNA from integrin-engaged cells degraded to 50% within 60 minutes, thus supporting the essential role of HuR in this stabilization event. To study inflammatory angiogenesis in vivo, we used a subcutaneous polyvinyl alcohol (PVA) sponge model to assess differences in wild-type and macrophage-specific conditional HuR knockout (HuRflox/floxLysM-Cre) mice. Flow cytometry analyses of cells extracted from PVA sponges at 1 to 4 weeks showed equal recruitment of F4/80+ cells in wild-type and HuR knockout mice. Immunofluorescence staining of excised PVA sponges confirmed equal macrophage recruitment and localization but revealed a reduction of VEGF production. Preliminary results indicate that formation of CD31+ microvessels in HuR knockout mice is also decreased. We conclude that macrophage â2-integrin engagement results in stabilization of VEGF and that expression of HuR in macrophages is required for neovascular responses. These findings are relevant to understanding the post-transcriptional regulatory mechanisms of inflammatory angiogenesis

Multimodal imaging of sarcoid choroidal granulomas

BACKGROUND: Enhanced-depth imaging optical coherence tomography (EDI-OCT) provides high-resolution imaging of the choroid. Herein, we report multimodal imaging, including EDI-OCT, of a case of sarcoid choroidal granulomas. FINDINGS: A 63-year-old female with biopsy-supported sarcoidosis presented with unilateral multifocal choroidal granulomas. Enhanced-depth imaging optical coherence tomography (EDI-OCT) demonstrated a homogenous hyporeflective choroidal lesion with choriocapillaris thinning and sparing of the surrounding choroid. The patient was started on oral steroids with a weekly taper schedule. Within 5 weeks, the choroidal lesions had clinically resolved with return of normal-appearing choroidal architecture on EDI-OCT. Indocyanine green angiography, however, demonstrated hypofluoresence at the sites of choroidal granulomas 11 months after the clinical resolution, suggesting a longstanding choroidal perfusion deficit undetected by OCT. CONCLUSIONS: Choroidal imaging via EDI-OCT provides detailed morphologic information of sarcoid granulomas and can accurately demonstrate structural resolution of the lesions

Idiopathic Unilateral Enlargement of the Extraocular Muscles in an Infant

The differential diagnosis for enlargement of the extraocular muscles (EOMs) generally includes infiltrative, inflammatory, and vascular processes. Herein, we report the unusual case of an infant who presented with unilateral restrictive strabismus secondary to idiopathic enlargement of the EOMs

Central Retinal Artery Occlusion: Acute Management and Treatment

This review will seek to answer if advances in ophthalmic imaging and evolution of treatment modalities have shed further light on the epidemiology, pathophysiology, diagnosis, and acute management of acute CRAO. Imaging characteristics of acute CRAO have been further characterized with the use of fluorescein angiography, optical coherence tomography (OCT), OCT-angiography, and indocyanine-green angiography. Layer segmentation of OCT imaging has found inner retinal layer hyper-reflectivity to be a common finding in acute CRAO. Non-invasive therapies, fibrinolytic delivery, and surgical interventions for acute CRAO have been further evaluated as potential management tools. A large body of literature reports very inconsistent treatment success with a wide variety of modalities. Currently, there is no clear evidence supporting the use of fibrinolytics in acute CRAO. Large, multicenter, randomized control trials are necessary to elucidate the role of the various acute treatment options in the management of CRAO

Multi-modal Imaging of Retinal Capillary Hemangioblastoma

Retinal capillary hemangioblastoma is the most frequent and earliest manifestation of Von Hippel Lindau disease, though they can be an isolated finding without systemic involvement. Although peripheral lesions are most common, juxtapapillary lesions are found in 11 to 15% of cases and can mimic pseudopapilledema, papillitis, or choroidal neovascular membrane. Here we present a case of retinal capillary hemangioblastoma masquerading as pseudopapilledema

Retinal Findings and Cardiovascular Risk: Prognostic Conditions, Novel Biomarkers, and Emerging Image Analysis Techniques

Many retinal diseases and imaging findings have pathophysiologic underpinnings in the function of the cardiovascular system. Myriad retinal conditions, new imaging biomarkers, and novel image analysis techniques have been investigated for their association with future cardiovascular risk or utility in cardiovascular risk prognostication. An intensive literature search was performed to identify relevant articles indexed in PubMed, Scopus, and Google Scholar for a targeted narrative review. This review investigates the literature on specific retinal disease states, such as retinal arterial and venous occlusions and cotton wool spots, that portend significantly increased risk of future cardiovascular events, such as stroke or myocardial infarction, and the implications for personalized patient counseling. Furthermore, conditions diagnosed primarily through retinal bioimaging, such as paracentral acute middle maculopathy and the newly discovered entity known as a retinal ischemic perivascular lesion, may be associated with future incident cardiovascular morbidity and are also discussed. As ever-more-sophisticated imaging biomarkers and analysis techniques are developed, the review concludes with a focused analysis of optical coherence tomography and optical coherence tomography angiography biomarkers under investigation for potential value in prognostication and personalized therapy in cardiovascular disease

Imaging human macular pigments with visible light optical coherence tomography and superluminescent diodes.

We demonstrate superluminescent diodes (SLDs) for visible light optical coherence tomography (OCT) of the human retina. SLDs are less costly than supercontinuum sources and have lower intrinsic excess noise, enabling imaging closer to the shot noise limit. While single SLDs are not broadband, they provide power concentrated at specific wavelengths relevant to retinal function. As a new, to the best of our knowledge, application, we image human macular pigments (MPs), which are thought to both aid vision and protect against advanced age-related macular degeneration. Using the unique depth-resolved capabilities of OCT, we localize MPs in depth to Henle's fibers beneath the foveal pit in the living human retina. Our approach reduces the cost of visible light OCT to nearly that of near-infrared (NIR) OCT while also providing information about clinically relevant MPs which cannot be measured in the NIR

Accidental Nd:YAG Laser–Induced Macular Hole in a Pediatric Patient

After being exposed to an industrial Nd:YAG laser, an 11-year-old boy developed a full-thickness macular hole in the right eye with resultant visual acuity of 20/100. Five months after the initial injury, the vision was stable and the hole was still present. The patient underwent pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade with prone positioning. Three months postoperatively, visual acuity improved to 20/25 with closure of the macular hole; however, there was a focal photoreceptor deficit. A review of the English-language literature identified 15 eyes with similar macular hole injuries after Nd:YAG exposure. Three eyes were surgically managed. While all holes were successfully closed, only two experienced visual improvement