Age‐related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk factor after smoking for progression to late‐stage NV AMD. To date, the mechanisms that underscore this observation remain ill‐defined. Given the impact of high‐fat diets on gut microbiota, we investigated whether commensal microbes influence the evolution of AMD. Using mouse models of NV AMD, microbiotal transplants, and other paradigms that modify the gut microbiome, we uncoupled weight gain from confounding factors and demonstrate that high‐fat diets exacerbate choroidal neovascularization (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low‐grade inflammation characteristic of inflammaging with elevated production of IL‐6, IL‐1β, TNF‐α, and VEGF‐A that ultimately aggravate pathological angiogenesis.
Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.
The deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight. We provide evidence from both human and animal studies for the critical role of the classical neuronal guidance cue, semaphorin 3A, in instigating pathological vascular permeability in diabetic retinas via its cognate receptor neuropilin-1. We reveal that semaphorin 3A is induced in early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. We demonstrate, by a series of orthogonal approaches, that neutralization of semaphorin 3A efficiently prevents diabetes-induced retinal vascular leakage in a stage of the disease when vascular endothelial growth factor neutralization is inefficient. These observations were corroborated in Tg(Cre-Esr1)/Nrp1(flox/flox) conditional knockout mice. Our findings identify a therapeutic target for macular edema and provide further evidence for neurovascular crosstalk in the pathogenesis of DR.
In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was initially isolated from hypothalamus extracts on the basis of its ability to stimulate the production of cAMP in cultured pituitary cells. Recent studies have shown that PACAP exerts potent neuroprotective effects not only in vitro but also in in vivo models of Parkinson's disease, Huntington's disease, traumatic brain injury and stroke. The protective effects of PACAP are based on its capacity to prevent neuronal apoptosis by acting directly on neurons or indirectly through the release of neuroprotective factors by astrocytes. These biological activities are mainly mediated through activation of the PAC1 receptor which is currently considered as a potential target for the treatment of neurodegenerative diseases. However, the use of native PACAP, the endogenous ligand of PAC1, as an efficient neuroprotective drug is actually limited by its rapid degradation. Moreover, injection of PACAP to human induces peripheral side effects which are mainly mediated through VPAC1 and VPAC2 receptors. Strategies to overcome these compromising conditions include the development of metabolically stable analogs of PACAP acting as selective agonists of the PAC1 receptor. This review presents an overview of the structure-activity relationships of PACAP and summarizes the molecular and conformational requirements for activation of PAC1 receptor. The applicability of PACAP analogs as therapeutic agents for treatment of neurodegenerative diseases is also discussed.
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