title: Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms.
abstract: While increased VEGF-A has been associated with neovascular age-related macular degeneration (AMD), it is not known whether VEGF-A may also promote other age-related eye diseases. Here, we show that an increase in VEGF-A is sufficient to cause multiple distinct common aging diseases of the eye, including cataracts and both neovascular and non-exudative AMD-like pathologies. In the lens, increased VEGF-A induces age-related opacifications that are associated with ERK hyperactivation, increased oxidative damage, and higher expression of the NLRP3 inflammasome effector cytokine IL-1β. Similarly, increased VEGF-A induces oxidative stress and IL-1β expression also in the retinal pigment epithelium (RPE). Targeting NLRP3 inflammasome components or Il1r1 strongly inhibited not only VEGF-A-induced cataract formation, but also both neovascular and non-exudative AMD-like pathologies. Moreover, increased VEGF-A expression specifically in the RPE was sufficient to cause choroidal neovascularization (CNV) as in neovascular AMD, which could be inhibited by RPE-specific inactivation of Flk1, while Tlr2 inactivation strongly reduced CNV. These findings suggest a shared pathogenic role of VEGF-A-induced and NLRP3 inflammasome-mediated IL-1β activation for multiple distinct ocular aging diseases.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA Department of Dermatology, Harvard Medical School, Boston, MA, USA amarneros@mgh.harvard.edu.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Marneros
mesh_terms: D000375:Aging; D000818:Animals; D004195:Disease Models, Animal; D005128:Eye Diseases / Q000473:pathology* / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D007908:Lens, Crystalline / Q000473:pathology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009389:Neovascularization, Pathologic; D012160:Retina / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: NLRP3 inflammasome; VEGF‐A; age‐related macular degeneration; aging; cataract