Caspase-8 Modulates Angiogenesis By Regulating A Cell Death Independent Pathway In Endothelial Cells
Tisch, N.; Freire-Valls, A.; Yerbes, R.; Paredes, I.; La Porta, S.; Wang, X.; Martin-Perez, R.; Castro, L.; Wei-Lynn Wong, W.; Coultas, L.; Strilic, B.; Groene, H.-J.; Hielscher, T.; Mogler, C.; Adams, R.; Heiduschka, P.; Claesson-Welsh, L.; Mazzone, M.; Lopez-Rivas, A.; Schmidt, T.; Augustin, H.; Ruiz de Almodovar, C.
Show abstract
During developmental angiogenesis blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and 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 both cell death via apoptosis and necroptosis. Here we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal angiogenesis. EC specific Casp-8 knockout pups (Casp-8ECko) have reduced retinal angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting and migration independent of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 mitogen-activated protein kinase (MAPK) downstream of receptorinteracting serine/threonine-protein kinase 3 (RIPK3) and destabilization of 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 is beneficial, as pathological neovascularization was reduced in Casp-8ECko pups. Taken together, we identify that Casp-8 signals in a cell-death independent manner in ECs during postnatal and pathological blood vessel formation.
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