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The formation of new blood vessels by angiogenesis is a key feature of several diseases including age-related macular degeneration, proliferative diabetic retinopathy (PDR), atherosclerosis, rheumatoid arthritis and cancer. The factors [...], Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-β1 (TGF-β1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-β accessory receptor endoglin, which, in the presence of TGF-β1, results in promotion of the pro-angiogenic Smad 1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-β signalling.

The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-[beta] (A[beta]) deposition, neuronal apoptosis, and cell loss. Here, we provide evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that A[beta] colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner. We demonstrate that targeting different components of the A[beta] formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo, and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the A[beta] pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the A[beta] pathway may be the most effective strategy in A[beta]-related diseases. combination therapy | neuroprotection | retinal ganglion cell apoptosis

Annexins are widely expressed [Ca.sup.2+] -dependent phospholipid-binding proteins with poorly understood physiological roles. Proposed functions include [Ca.sup.2+] channel activity and vesicle trafficking, but neither have been proven in vivo. Here we used targeted gene disruption to generate B-lymphocytes lacking annexin 5 (Anx5) expression and show that this results in reduced susceptibility to a range of apoptotic stimuli. By comparison B-lymphocytes lacking annexin 2 (Anx2) showed no such resistance, providing evidence that this effect is specific to loss of Anx5. The defect in the [ANX5.sup.-1] -cells occurs early in the apoptotic program before nuclear condensation, caspase 3 activation, and cell shrinkage, but downstream of an initial [Ca.sup.2+] influx. Only UVA/B irradiation induced similar levels of apoptosis in wild-type and [ANX5.sup.-1] -cells. Unexpectedly, [ANX5.sup.-1] cells permeabilized in vitro also failed to release mitochondrial cytochrome C, suggesting a possible mechanism for their resistance to apoptosis. These findings demonstrate a role for Anx5 in determining the susceptibility of B-lymphocytes to apoptosis.

Gerke, Volker, and Stephen E. Moss. Annexins: From Structure to Function. Physiol Rev 82: 331-371, 2002; 10.1152/physrev.00030.2001.--Annexins are [Ca.sup.2+] and phospholipid binding proteins forming an evolutionary conserved multigene family with [...]