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Caspase-8 modulates physiological and pathological angiogenesis during retina development
Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, Heidelberg, Germany.
Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany.
Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Univ Seville, CSIC, Ctr Andaluz Biol Mol & Med Regenerat CABIMER, Seville, Spain;Univ Pablo Olavide, Seville, Spain.
Heidelberg Univ, Biochem Ctr, Heidelberg, Germany;Heidelberg Univ, European Ctr Angiosci ECAS, Heidelberg, Germany;Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, Heidelberg, Germany.
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2019 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 129, no 12, p. 5092-5107Article in journal (Refereed) Published
Abstract [en]

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-8(ECKO)) 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.

Place, publisher, year, edition, pages
AMER SOC CLINICAL INVESTIGATION INC , 2019. Vol. 129, no 12, p. 5092-5107
National Category
Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-400683DOI: 10.1172/JCI122767ISI: 000500567600012PubMedID: 31454332OAI: oai:DiVA.org:uu-400683DiVA, id: diva2:1382165
Funder
EU, European Research Council, ERC-StG-311367Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved

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Claesson-Welsh, Lena

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