Remodeling senescent blood vessels: The retina is a thin layer of nervous tissue at the back of the eye that transforms light into neuronal signals. The retina is essential for vision and is supported by networks of blood vessels. In diabetic retinopathy, a common cause of vision loss, these microvessels degenerate and regrow in an aberrant manner. Such degeneration and regrowth can compromise the functioning of retinal nerve cells. Binet et al. observed that, after rapid proliferation, vascular endothelial cells in diseased blood vessels engaged molecular pathways linked to cellular senescence (see the Perspective by Podrez and Byzova). Senescent vascular units summoned an inflammatory response in which neutrophils extruded neutrophil extracellular traps onto diseased vessels to remodel them. This endogenous repair mechanism promoted the elimination of senescent blood vessels and could lead to beneficial vascular remodeling. Science , this issue p. eaay5356 ; see also p. 919

Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid, acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively enhance accessibility at binding sites for activator protein-1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, ultimately leading to proinflammatory cytokine transcription, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes to neuroinflammation.

Significance: Diabetic retinopathy is a major cause of blindness in the working population. The most common cause of visual impairment in diabetic patients is diabetic macular edema (DME). Roughly 40% of patients with DME respond poorly to anti-VEGF therapies, which are a standard of care. Here we provide mechanistic insight for the critical role of NOTCH1 signaling in compromising endothelial junction integrity during diabetes. Besides activating canonical transcriptional pathways, we find that NOTCH1 signaling also provokes disruption of endothelial junctions via noncanonical mechanisms, such as production of nitric oxide and activation of Src signaling, leading to vascular endothelial-cadherin and β-catenin dissociation. Our findings have implications for future therapeutic interventions given that we find elevated NOTCH1 ligands in the vitreous of patients with DME and that their neutralization decreases pathologic vascular permeability.

Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic association between genes of innate immunity and AMD, genome-to-phenome relationships are low, suggesting a critical contribution of environmental triggers of disease. Possible insight comes from the observation that a past history of infection with pathogens such as Chlamydia pneumoniae, or other systemic inflammation, can predispose to nvAMD in later life. Using a mouse model of nvAMD with prior C. pneumoniae infection, endotoxin exposure, and genetic ablation of distinct immune cell populations, we demonstrated that peripheral infections elicited epigenetic reprogramming that led to a persistent memory state in retinal CX3CR1⁺ mononuclear phagocytes (MNPs). The immune imprinting persisted long after the initial inflammation had subsided and ultimately exacerbated choroidal neovascularization in a model of nvAMD. Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identified activating transcription factor 3 (ATF3) as a central mediator of retina-resident MNP reprogramming following peripheral inflammation. ATF3 polarized MNPs toward a reparative phenotype biased toward production of proangiogenic factors in response to subsequent injury. Therefore, a past history of bacterial endotoxin–induced inflammation can lead to immunological reprograming within CNS-resident MNPs and aggravate pathological angiogenesis in the aging retina.

Changes in cell function occur by specific patterns of intracellular Ca²⁺, activating Ca²⁺-sensitive proteins. The anoctamin (TMEM16) protein family has Ca²⁺-dependent ion channel activity, which provides transmembrane ion transport, and/or Ca²⁺-dependent phosphatidyl-scramblase activity. Using amino acid sequence analysis combined with measurements of ion channel function, we clarified the so far unknown Ano4 function as Ca²⁺-dependent, non-selective monovalent cation channel; heterologous Ano4 expression in HEK293 cells elicits Ca²⁺ activated conductance with weak selectivity of K⁺ > Na⁺ > Li⁺. Endogenously expressed Ca²⁺-dependent cation channels in the retinal pigment epithelium were identified as Ano4 by KO mouse-derived primary RPE cells and siRNA against Ano4. Exchanging a negatively charged amino acid in the putative pore region (AA702–855) into a positive one (E775K) turns Ano4-elicited currents into Cl⁻ currents evidencing its importance for ion selectivity. The molecular identification of Ano4 as a Ca²⁺-activated cation channel advances the understanding of its role in Ca²⁺ signaling.