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Gogiraju, R.* ; Moiko, K.* ; Bochenek, M.L.* ; Greulich, F.* ; Witzler, C.* ; Schmitz, W.* ; Zifkos, K.* ; Derieux, C.* ; Ghasemi, I.* ; Guliani, P.* ; Sun, B.* ; Espinola-Klein, C.* ; Uhlenhaut, N.H. ; Bock, A.* ; Ruf, W.* ; Madhusudhan, T.* ; Lurz, P.* ; Schäfer, K.*

Lysed erythrocyte membranes metabolically prime endothelial cells for angiogenesis.

Angiogenesis 29:74 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Endothelial dysfunction is a hallmark of pathological angiogenesis and associated with erythrocyte extravasation and lysis. Whether mediators released from lysed erythrocytes instruct endothelial cells (ECs) for new vessel formation is unknown. Here, we show that the membrane fraction of lysed erythrocytes activates inflammatory endothelial gene transcription and metabolically reprograms ECs to promote angiogenic sprout formation. Alterations in endothelial glucose metabolism occurred downstream of NFκB p65 activation by extracellular ATP via fast-acting endothelial P2X7 receptors and also involved ATP-mediated adenylyl cyclase activation and cyclic AMP generation via P2RY11. Overexpression and acetylation of histone 3 at lysine 27 of NR4A1 was identified as anti-inflammatory control mechanism and angio-metabolic switch activating VEGF, PFKFB3 and other AP-1 dependent gene transcription programs. The angiogenic potential of lysed erythrocyte membranes from patients with peripheral artery disease was impaired and could be restored by inhibiting endothelial phosphodiesterase 4 to prevent endothelial cAMP degradation. Our findings uncover that erythrolysis metabolically primes ECs for angiogenesis and that targeting endothelial cAMP generation may be a promising strategy to restore endothelial angiogenic functions.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Angiogenesis ; Cardiovascular Disease ; Endothelial Cells ; Erythrocytes ; Inflammation ; Metabolism ; Peripheral Artery Disease; Nf-kappa-b; Peripheral Artery-disease; Orphan Nuclear Receptors; Extracellular Atp; Transcriptional Regulators; Cyclic-amp; P65; Expression; Mechanism; Release
ISSN (print) / ISBN 0969-6970
e-ISSN 1573-7209
Journal Angiogenesis
Quellenangaben Volume: 29, Issue: 4, Pages: , Article Number: 74 Supplement: ,
Publisher Springer
Publishing Place Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Endocrinology (IDE)
Grants Else Krner-Fresenius-Stiftung
Deutsches Zentrum fr Herz-Kreislaufforschung
Bundesministerium fr Forschung, Technologie und Raumfahrt
European Research Council
Deutsche Forschungsgemeinschaft