Tisch, NathalieFreire-Valls, AidaYerbes, RosarioParedes, IsidoraLa Porta, SilviaWang, XiaohongMartín-Pérez, RosaCastro, LauraWong, Wendy Wei-LynnCoultas, LeighStrilic, BorisGröne, Hermann-JosefHielscher, ThomasMogler, CarolinAdams, Ralf HHeiduschka, PeterClaesson-Welsh, LenaMazzone, MassimilianoLópez-Rivas, AbelardoSchmidt, ThomasAugustin, Hellmut GRuiz de Almodovar, Carmen2023-01-252023-01-252019http://hdl.handle.net/10668/14448During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-8ECKO) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.enAngiogenesisApoptosis pathwaysCaspases and caspase substratesRetinopathyAnimalsAnimals, NewbornAntigens, CDCadherinsCaspase 8Cell DeathCell MovementCell ProliferationEndothelial CellsFemaleHuman Umbilical Vein Endothelial CellsHumansLungMiceMice, KnockoutNecroptosisNeovascularization, PathologicNeovascularization, PhysiologicOxygenPhosphorylationReceptor-Interacting Protein Serine-Threonine KinasesRetinaSignal Transductionp38 Mitogen-Activated Protein Kinasesresearch article31454332open access10.1172/JCI1227671558-8238PMC6877326http://www.jci.org/articles/view/122767/files/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877326/pdf