[Wernicke encephalopathy : a neuro-ophthalmological side effect of bariatric surgery]. / L'encéphalopathie de Gayet-Wernicke : une complication neuro-ophtalmologique de la chirurgie bariatrique.

Due to an increase in the worldwide prevalence of obesity and the efficiency of bariatric surgery, this procedure is more often performed. Besides its benefits, it has also disadvantages and may be the cause of nutritional deficiencies. Thiamin deficiency is particularly important to diagnose and to treat early as it can lead to major sequelae and even to death. Wernicke's encephalopathy is the most frequent presentation associating confusion, ataxia, ophtalmoplegia and nystagmus. The full triad is not usually observed, which may lead to sub-diagnosis of this affection. The diagnosis is clinical, biological and radiologic thanks to the brain MRI. Intravenous thiamin supplementation therapy must be administered as fast as possible in order to avoid long-term damages. In the ophthalmological field, the potential sequelae are ophthalmoplegia, nystagmus and optic neuropathy. Therapeutics for nystagmus are pharmacological, surgical and/or optical. We illustrate this condition with a case report of an 18-year-old man developing Wernicke's encephalopathy as early as six weeks after a sleeve gastrectomy.

Suite à une augmentation de la prévalence de l'obésité dans le monde et à l'efficacité de la chirurgie bariatrique, cette technique est pratiquée de plus en plus fréquemment. Malgré ses avantages, elle n'est pas sans risque et peut être responsable de déficits nutritionnels multiples. Le déficit en vitamine B1 ou thiamine est particulièrement important à connaître et, à rapidement diagnostiquer en raison des nombreuses séquelles invalidantes, voire le décès du patient, dont il peut être responsable. Le tableau classique est l'encéphalopathie de Gayet-Wernicke associant confusion, ataxie et troubles oculomoteurs. Néanmoins, il n'est pas toujours complet, ce qui participe au sous-diagnostic de cette pathologie. Le diagnostic est clinique, biologique et/ou radiologique grâce à l'IRM cérébrale. La supplémentation vitaminique intraveineuse doit être instaurée le plus rapidement possible afin d'éviter des séquelles à long terme. D'un point de vue ophtalmologique, les séquelles potentielles sont les ophtalmoplégies, les nystagmus et les neuropathies optiques. Les thérapies envisageables du nystagmus, outre la supplémentation en thiamine en aigu, sont pharmacologiques, chirurgicales et/ou optiques. Nous illustrons cette pathologie par un cas clinique d'encéphalopathie de Gayet-Wernicke dès la 6ème semaine post-opératoire d'une chirurgie bariatrique de type «sleeve¼ chez un patient de 18 ans.

Utility of ganglion cells for the evaluation of anterior visual pathway pathology: a review.

The management of optic neuropathy is fundamental to neuro-ophthalmic practice. Following the invention of the ophthalmoscope, clinicians, for a century or more, relied upon fundus examination in the evaluation of optic neuropathy. However, the advent of optical coherence tomography, based on the principle of backscattering of light and interferometry, has revolutionized the analysis of optic nerve and retinal disorders. Optical coherence tomography has proven of particular value in the measurement, at the micron level, of the peripapillary retinal nerve fibre layer and the ganglion cell layer. These measurements have proven critical in the differential diagnosis and monitoring of optic neuropathy. Specifically, thinning of the peripapillary nerve fibre layer provides evidence of axonal loss affecting any sector of the optic nerve. Thinning of the macular ganglion cell layer, on the other hand, shows a more precise correlation with visual deficits due to retrograde degeneration following optic nerve damage, although limited to central retina. In daily practise, optical coherence tomography is of great value in assessing the diagnosis, prognosis and response to treatment in optic neuropathy. Particular advances have been made, for example, in the assessment of optic neuritis, papilloedema and chiasmal compression which have translated to everyday practice. As with any other imaging technology the clinician must have a clear understanding of acquisition artefacts. A further issue is the relatively limited normative database in sub-populations such as the young and individuals with a refractive error > + 5 or < -5 dioptres.

The Occurrence of Intraretinal and Subretinal Fluid in Anterior Ischemic Optic Neuropathy: Pathogenesis, Prognosis, and Treatment.

PURPOSE: To describe the frequency and characteristics of intraretinal and subretinal fluid in nonarteritic anterior ischemic optic neuropathy (NAAION) and to assess the influence on the visual deficit and optic nerve fiber/ganglion cell loss. DESIGN: A retrospective, single-center study. PARTICIPANTS: Thirty-two patients with NAAION referred to our Neuro-ophthalmology Department between 2014 and 2021. METHODS: The study was carried out at the University Hospital of Liège, Belgium. For participants in whom subretinal fluid was identified on standard OCT (Carl Zeiss Meditec) an additional macular OCT (Spectralis Heidelberg) had been performed. The pattern and the maximal height of the retinal fluid were determined manually, and thicknesses of retinal layers were obtained using the OCT protocol analysis. RESULTS: The mean age of the cohort was 60 years (standard deviation, ±12.5; range, 22-88 years), and 65.6% were male. In the 21 eyes (46.7%) in which retinal fluid was observed, macular OCT findings were categorized according to fluid localization: 19 cases had parafoveal fluid (of whom 9 also had subfoveal fluid). One patient had subfoveal fluid alone, and 1 patient had peripapillary subretinal fluid alone. Specific patterns of optic disc (OD) swelling were associated with the occurrence and distribution of retinal edema. Visual acuity, visual field loss, and foveal thresholds were stable over the period of observation (P = 0.74, P = 0.42, and P = 0.36, respectively). No difference was found in visual function at 6 months between patients with retinal fluid treated (n = 10) or not treated (n = 11) with corticosteroids (visual acuity, P = 0.13; foveal threshold, P = 0.59; mean deviation, P = 0.66). CONCLUSIONS: Subretinal fluid is found in a high proportion of cases of NAAION. Visual function remained largely stable from presentation in this cohort. Corticosteroid intake at presentation did not influence visual recovery or timing of the resorption of tissue edema. Our findings do not support treatment of NAAION with corticosteroids with or without evidence of subretinal fluid acutely. With regard to pathogenesis, we propose that the volume of transudate generated at the OD is the critical factor rather than dysfunction of retinal mechanisms subserving reabsorption. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Candida chorioretinitis in renal transplant recipient with candidemia related to contaminated organ preservation fluid: A role for dilated fundus examination in its management.

Infection by Candida spp is a potentially life-threatening condition among both immunocompromised and immunocompetent patients. Candida chorioretinitis can occur as a complication of candidemia and may develop into endophthalmitis if not detected and treated early, which can lead to irreversible visual loss. Here, we report on a 52-year-old diabetic woman who developed candidemia complicated by bilateral chorioretinitis following kidney transplantation. Antifungal therapy was immediately started but fundoscopic examination highlighted multiple bilateral chorioretinal lesions. Given new onset of vomiting and increased number of retinal lesions on repeat fundus examination a few weeks later, the patient underwent a positron emission tomography (PET) which revealed a mycotic arterial pseudoaneurysm at the renal graft anastomosis. It led ineluctably to transplantectomy, aneurysm flattening and vascular reconstruction a few days later. Blood cultures remained negative and fundus examination progressively showed a regression of chorioretinal lesions until their complete disappearance a few months later. Our case emphasizes the importance of a non-invasive examination which allowed to accelerate and optimize in a consequential way the management of the patient leading to her recovery after a long antifungal treatment.

Comparing the transcriptome of developing native and iPSC-derived mouse retinae by single cell RNA sequencing.

We report the generation and analysis of single-cell RNA-Seq data (> 38,000 cells) from mouse native retinae and induced pluripotent stem cell (iPSC)-derived retinal organoids at four matched stages of development spanning the emergence of the major retinal cell types. We combine information from temporal sampling, visualization of 3D UMAP manifolds, pseudo-time and RNA velocity analyses, to show that iPSC-derived 3D retinal organoids broadly recapitulate the native developmental trajectories. However, we observe relaxation of spatial and temporal transcriptome control, premature emergence and dominance of photoreceptor precursor cells, and susceptibility of dynamically regulated pathways and transcription factors to culture conditions in retinal organoids. We demonstrate that genes causing human retinopathies are enriched in cell-type specifying genes and identify a subset of disease-causing genes with expression profiles that are highly conserved between human retinae and murine retinal organoids. This study provides a resource to the community that will be useful to assess and further improve protocols for ex vivo recapitulation and study of retinal development.

Nonarteritic Anterior Ischemic Optic Neuropathy: Cystic Change in the Inner Nuclear Layer Caused by Edema and Retrograde Maculopathy.

Purpose: Microcystic macular edema (MME), also known as retrograde maculopathy (RM), is associated with severe optic atrophy because of a range of causes. However, similar changes have also been described in primary retinal pathology and the pathogenesis of MME is debated. Design: A retrospective observational case series. Participants: Patients with nonarteritic ischemic optic neuropathy. Methods: A retrospective observational case series was performed at the University Hospital of Liège, Belgium. The medical records of patients who were referred to our Neuro-ophthalmology department with a diagnosis of nonarteritic anterior ischemic optic neuropathy (NA-AION), between 2014 and 2021, were reviewed. Main Outcome Measures: Ganglion cell complex thickness, acute and chronic inner nuclear change. Results: In a cohort of 34 patients (mean age: 60 ± 12.5 years; 65.6% men) with NA-AION, we identified a transient microcystic change in the inner nuclear layer (INL) associated with optic disc swelling in 19 eyes at presentation. This early change was associated with a transudate of intraretinal and subretinal fluid originating from the optic disc. Among patients who had shown this transient change 3 subsequently developed MME, which remained fixed during the period of observation (range, 12-34 months). No MME was observed in patients without an early INL transient change. Microcystic macular edema was observed in patients with severe ganglion cell complex thinning at 6 months: mean (± SD) loss in superior hemimacula (-28.2 ± 5.2 µm [-33.3%, range, -22.3 to -30.3 µm]) and in inferior hemimacula (-30.7 ± 5.6 µm [-31.0%, range, -24.3 to 34.8 µm]). Conclusions: Our study has revealed 2 causes of INL cystic change in the same patients experiencing NA-AION, 1 reversible and the other likely permanent. This finding highlights the distinction between genuine edema related to transudation of fluid (in this case secondary to ischemic optic disc swelling) and the phenomenon observed in RM that is related to the degree of retinal nerve fiber layer/ganglion cell complex thinning. Cystic change in the INL is associated with severe optic atrophy (MME). However, similar changes have been described in retinal pathology and the pathogenesis of MME is debated.

Drones' side effect: facial and ocular trauma caused by an aerial drone.

An adult man was struck in the face by his own aerial drone. The propellers hit the upper face region leading to forehead and eyelid lacerations, a partial scleral laceration, conjunctival laceration, hyphaema, traumatic iritis and forward displacement of one haptic of the intraocular lens from a previous cataract surgery. In the last decade, drone use has significantly increased and drone-related injuries have become an emerging cause of trauma. Our case raises awareness of the risks and highlights the need for improvement in regulation of drone use.

Pyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics.

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow-derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. KEY MESSAGES: Lactate and lipoprotein profile are associated with the active phase of AMD and CNV development. Lactate is a relevant and functional metabolite correlated with AMD progression. Modulating lactate through pyruvate dehydrogenase kinase led to a decrease of CNV progression. Pyruvate dehydrogenase kinase is a new therapeutic target for neovascular AMD.

Recognition memory for colored and black-and-white scenes in normal and color deficient observers (dichromats).

Color deficient (dichromat) and normal observers' recognition memory for colored and black-and-white natural scenes was evaluated through several parameters: the rate of recognition, discrimination (A'), response bias (B"D), response confidence, and the proportion of conscious recollections (Remember responses) among hits. At the encoding phase, 36 images of natural scenes were each presented for 1 sec. Half of the images were shown in color and half in black-and-white. At the recognition phase, these 36 pictures were intermixed with 36 new images. The participants' task was to indicate whether an image had been presented or not at the encoding phase, to rate their level of confidence in his her/his response, and in the case of a positive response, to classify the response as a Remember, a Know or a Guess response. Results indicated that accuracy, response discrimination, response bias and confidence ratings were higher for colored than for black-and-white images; this advantage for colored images was similar in both groups of participants. Rates of Remember responses were not higher for colored images than for black-and-white ones, whatever the group. However, interestingly, Remember responses were significantly more often based on color information for colored than for black-and-white images in normal observers only, not in dichromats.

Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice.

The mouse model of laser-induced choroidal neovascularization (CNV) has been used extensively in studies of the exudative form of age-related macular degeneration (AMD). This experimental in vivo model relies on laser injury to perforate Bruch's membrane, resulting in subretinal blood vessel recruitment from the choroid. By recapitulating the main features of the exudative form of human AMD, this assay has served as the backbone for testing antiangiogenic therapies. This standardized protocol can be applied to transgenic mice and can include treatments with drugs, recombinant proteins, antibodies, adenoviruses and pre-microRNAs to aid in the search for new molecular regulators and the identification of novel targets for innovative treatments. This robust assay requires 7-14 d to complete, depending on the treatment applied and whether immunostaining is performed. This protocol includes details of how to induce CNV, including laser induction, lesion excision, processing and different approaches to quantify neoformed vasculature.

Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study.

INTRODUCTION: The aim of this study was to examine ranibizumab treatment patterns in "real-world" practice and clinical settings, as well as to assess quality of life outcomes over a 24-month period. MATERIALS AND METHODS: This was a prospective, observational, multicenter, open-label study of 0.5 mg of ranibizumab administered intravitreally. Patients were followed over 24 ± 3 months with intermediate data points at 6 ± 2 months and 12 ± 2 months, and a limited data point at 2.5 ± 1 month that coincided with the end of the loading phase. Outcomes included visual acuity (Early Treatment Diabetic Retinopathy Study), visual function (National Eye Institute Visual Function Questionnaire-25 [NEI VFQ-25]), quality of life (Health Utilities Index Mark III [HUI3]), and safety. RESULTS: A total of 267 patients with wet age-related macular degeneration (mean ± standard deviation [SD] age = 78.5 ± 7.3 years; 62.4% were female; 34.5% with dual eye involvement; 74.9% were treatment-naïve) were treated (309 eyes were treated). The mean ± SD Early Treatment Diabetic Retinopathy Study score at baseline was 56.3 ± 14.3 letters. The mean ± SD number of injections over 24 months was 7.6 ± 4.1, including 2.5 ± 0.7 and 5.9 ± 3.6 during the loading and maintenance phases, respectively, with corresponding treatment intervals of 4.8 ± 1.4 weeks and 11.5 ± 9.5 weeks, respectively. Improvements in visual acuity over baseline were reached at 2.5 months and maintained at 6 months (both P < 0.0001). The mean visual acuity increase over baseline at 12 months was not significant (P = 0.08); the decline over baseline at 24 months statistically significant (P = 0.02). Overall, 94.3% of patients showed stable or improved disease at 6 months and 81.5% of patients showed stable or improved disease at 24 months. At 6 months, improvements over baseline were significant for VFQ-25 (P = 0.03) and HUI3 (P = 0.02), but not at 12 months and 24 months. Improvements in VFQ-25 and HUI3 were maintained at 24 months in 38% and 34% of patients, respectively. In total 78 serious adverse events were reported in 40 patients and 77 nonserious adverse events in 34 patients. Nine serious adverse events and nine nonserious adverse events in 14 patients were suspected to be related to ranibizumab treatment. CONCLUSION: The "real-world" clinical effectiveness of ranibizumab was evidenced by the initial improvements over baseline in visual acuity and quality of life, as well as the maintenance of these outcomes at baseline levels at 24 months, and this was observed under variable treatment conditions. The findings underscore the need for individualized treatment with regular monitoring to achieve optimal vision and quality of life outcomes.

Sunitinib inhibits inflammatory corneal lymphangiogenesis.

PURPOSE: To evaluate the antilymphangiogenic potential of multi-target tyrosine kinase inhibitor sunitinib in corneal neovascularization (NV). METHODS: Inflammatory corneal NV was induced by thermal cauterization applied in the central cornea of mice, to which sunitinib malate was daily administered by gavage or not. At days 6, 11, or 17 post cauterization, lymphatic and blood vessels, as well as inflammatory cells were immunostained and quantified in whole-mounted corneas. RT-PCRs were performed to evidence VEGF-A, VEGF-C, VEGF-D, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor (VEGFR)-1 and -2 (sVEGFR-1, sVEGFR-2) expressions. Macrophages were isolated from mice peritoneal cavity following thioglycollate injection to produce conditioned medium. The effects of sunitinib were evaluated in vitro in the aortic and lymphatic ring assays in the presence or not of macrophage conditioned medium. RESULTS: Sunitinib treatment drastically reduced pathologic corneal lymphangiogenesis and angiogenesis. Reduced F4/80+ cell infiltration was evidenced in sunitinib-treated mice and was associated to decreased VEGF-A (by 50%, P < 0.01) and VEGF-C (by 35%, P < 0.01) expressions, while VEGF-D and sVEGFR-2 expressions were not affected. In vitro, sunitinib dose-dependently inhibited aortic ring outgrowth, but failed to affect lymphangiogenesis in the lymphatic ring assay. However, macrophage conditioned medium-enhanced angiogenesis and lymphangiogenesis were both strongly counteracted by sunitinib treatment. Mechanistically, sunitinib blocked VEGFR-2 phosphorylation induced by VEGF-A released by macrophages. CONCLUSIONS: Sunitinib exerts antihemangiogenic and antilymphangiogenic effects in vivo by reducing F4/80+ cell recruitment and interacting with their released factors.

Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells.

BACKGROUND: MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated. METHODOLOGY/PRINCIPAL FINDINGS: We first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization. CONCLUSIONS/SIGNIFICANCE: Our results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB.

Bone marrow-derived mesenchymal cells and MMP13 contribute to experimental choroidal neovascularization.

In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a neovascularisation into the choroid. RT-PCR analysis revealed that human neovascular membranes issued from patients with AMD expressed high levels of Mmp13. The contribution of MMP13 in choroidal neovascularization (CNV) formation was explored by using a murine model of laser-induced CNV and applying it to wild-type mice (WT) and Mmp13-deficient mice (Mmp13 ( -/- ) mice). Angiogenic and inflammatory reactions were explored by immunohistochemistry. The implication of bone marrow (BM)-derived cells was determined by BM engraftment into irradiated mice and by injecting mesenchymal stem cells (MSC) isolated from WT BM. The deficiency of Mmp13 impaired CNV formation which was fully restored by WT BM engraftment and partially rescued by several injections of WT MSC. The present study sheds light on a novel function of MMP13 during BM-dependent choroidal vascularization and provides evidence for a role for MSC in the pathogenesis of CNV.

Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

Frosted branch angiitis with undiagnosed Hodgkin lymphoma.

PURPOSE: To report the case of a patient with bilateral frosted branch angiitis and undiagnosed Hodgkin lymphoma. METHODS: Review of clinical history, laboratory findings, histology of supraclavicular lymph node biopsy, and follow-up. RESULTS: A 22-year-old man presented with a sudden, bilateral visual loss. Fundus examination and fluorescein angiography disclosed a bilateral frosted branch angiitis that was dramatically responsive to systemic corticosteroid therapy. Laboratory tests were unremarkable but radiologic studies showed extensive mediastinal and supraclavicular lymphadenopathy. A supraclavicular lymph node biopsy led to the diagnosis of nodular sclerosis Hodgkin lymphoma. CONCLUSIONS: The occurrence of frosted branch angiitis in combination with classical Hodgkin lymphoma, although possibly coincidental, raises the possibility of a paraneoplastic syndrome. Thus, we suggest that, for patients with frosted branch angiitis, Hodgkin lymphoma should be considered in the diagnostic workup.

Tumoral and choroidal vascularization: differential cellular mechanisms involving plasminogen activator inhibitor type I.

An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1(-/-) mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1(-/-) BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis.

Angiogenesis is not impaired in connective tissue growth factor (CTGF) knock-out mice.

Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors. CTGF is important in scarring, wound healing, and fibrosis. It has also been implicated to play a role in angiogenesis, in addition to vascular endothelial growth factor (VEGF). In the eye, angiogenesis and subsequent fibrosis are the main causes of blindness in conditions such as diabetic retinopathy. We have applied three different models of angiogenesis to homozygous CTGF(-/-) and heterozygous CTGF(+/-) mice to establish involvement of CTGF in neovascularization. CTGF(-/-) mice die around birth. Therefore, embryonic CTGF(-/-), CTGF(+/-), and CTGF(+/+) bone explants were used to study in vitro angiogenesis, and neonatal and mature CTGF(+/-) and CTGF(+/+) mice were used in models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. Angiogenesis in vitro was independent of the CTGF genotype in both the presence and the absence of VEGF. Oxygen-induced vascular pathology in the retina, as determined semi-quantitatively, and laser-induced choroidal neovascularization, as determined quantitatively, were also not affected by the CTGF genotype. Our data show that downregulation of CTGF levels does not affect neovascularization, indicating distinct roles of VEGF and CTGF in angiogenesis and fibrosis in eye conditions.