Blockade of Annexin A2 Prevents Early Microvasculopathy in Murine Models of Diabetic Retinopathy.

Purpose: We examined the role of annexin A2 (A2) in the development of diabetic retinal vasculopathy by testing the effect of Anxa2 gene deletion as well as administration of anti-A2 antibodies on pericyte dropout and retinal neovascularization in diabetic Akita mice, and in mice subjected to oxygen-induced retinopathy.

Methods: We analyzed diabetic Ins2AKITA mice with or without global deletion of Anxa2, as well as Ins2AKITA mice that received intravitreal anti-A2 IgG or control antibody at 2, 4, and 6 months, for retinal pericyte dropout at 7 months of age. In addition, we assessed the effect of intravitreal anti-A2 on oxygen-induced retinopathy (OIR) in neonatal mice by quantifying retinal neovascular and vaso-obliterative area, and by enumeration of neovascular tufts.

Annexin A2 Loss After Cardiopulmonary Bypass and Development of Acute Postoperative Respiratory Dysfunction in Children.

Unlabelled: The primary objective of this study was to determine whether expression of the multifunctional and adherens junction-regulating protein, annexin A2 (A2), is altered following cardiopulmonary bypass (CPB). A secondary objective was to determine whether depletion of A2 is associated with post-CPB organ dysfunction in children.

Design: In a prospective, observational study conducted over a 1-year period in children undergoing cardiac surgery requiring CPB, we analyzed A2 expression in peripheral blood mononuclear cells at different time points.

Lipofuscin causes atypical necroptosis through lysosomal membrane permeabilization.

Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes.

Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases.

Relative or absolute hypoxia activates signaling pathways that alter gene expression and stabilize the pulmonary microvasculature. Alveolar hypoxia occurs in disorders ranging from altitude sickness to airway obstruction, apnea, and atelectasis. Here, we report that the phospholipid-binding protein, annexin A2 (ANXA2) functions to maintain vascular integrity in the face of alveolar hypoxia.

Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells.

The annexins are an evolutionarily conserved family of phospholipid-binding proteins of largely unknown function. We observed that the AnxA2(-/-) lung basement membrane specifically lacks collagen VI (COL6), and postulated that ANXA2 directs bronchial epithelial cell secretion of COL6, an unusually large multimeric protein. COL6 serves to anchor cells to basement membranes and, unlike other collagens, undergoes multimerization prior to secretion.

The perivascular niche regulates breast tumour dormancy.

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain.

Hypoxia-inducible factor-1 drives annexin A2 system-mediated perivascular fibrin clearance in oxygen-induced retinopathy in mice.

Oxygen-induced retinopathy (OIR) is a well-characterized model for retinopathy of prematurity, a disorder that results from rapid microvascular proliferation after exposure of the retina to high oxygen levels. Here, we report that the proliferative phase of OIR requires transcriptional induction of the annexin A2 (A2) gene through the direct action of the hypoxia-inducible factor-1 complex. We show, in addition, that A2 stabilizes its binding partner, p11, and promotes OIR-related angiogenesis by enabling clearance of perivascular fibrin.

Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysis.

When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 muM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed "A2") is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the "tail" domain of A2.

Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling.

Retinoblastomas result from the inactivation of the RB1 gene and the loss of Rb protein, yet the cell type in which Rb suppresses retinoblastoma and the circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of postmitotic cone precursors but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells.

Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis.

The integrin receptor alphavbeta5 controls two independent forms of interactions of the retinal pigment epithelium (RPE) with adjacent photoreceptor outer segments that are essential for vision. Alphavbeta5 localizes specifically to apical microvilli of the RPE and contributes to retinal adhesion that maintains RPE contacts with intact outer segments at all times. Additionally, alphavbeta5 synchronizes diurnal bursts of RPE phagocytosis that clear photoreceptor outer segment fragments (POS) shed in a circadian rhythm.

Optic nerve tissue shrinkage during pathologic processing after enucleation for retinoblastoma.

Objectives: To quantify and analyze the differences between the length of the optic nerve as measured by the ophthalmologist in the operating room after enucleation and the length as measured by the pathologist after fixation.

Methods: The authors performed a retrospective review of patients who underwent either primary or secondary enucleation for retinoblastoma at the Ophthalmic Oncology Center of the New York-Presbyterian Hospital-Cornell campus between November 1979 and August 2001. Intraoperative notes and pathologic reports were reviewed to determine the length of the resected optic nerve as recorded by both the surgeon and pathologist.