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Tisch N, Freire-Valls A, Yerbes R, Paredes I, La Porta S, Wang X, Martín-Pérez R, Castro L, Wong WW, Coultas L, Strilic B, Gröne HJ, Hielscher T, Mogler C, Adams RH, Heiduschka P, Claesson-Welsh L, Mazzone M, López-Rivas A, Schmidt T, Augustin HG, Ruiz de Almodovar C
J. Clin. Invest. 129 (12) 5092-5107 [2019-12-02; online 2019-08-28]
During 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.
PubMed 31454332
DOI 10.1172/JCI122767
Crossref 10.1172/JCI122767
pmc: PMC6877326
pii: 122767