Lysed erythrocyte membranes metabolically prime endothelial cells for angiogenesis
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.
Authors
- Katrin Schäfer (ORCID: https://orcid.org/0000-0003-0846-4718)
- Rajinikanth Gogiraju (ORCID: https://orcid.org/0000-0003-1284-9338)
- Wolfram Ruf (ORCID: https://orcid.org/0000-0002-6064-2166)
- Magdalena L. Bochenek (ORCID: https://orcid.org/0000-0001-5577-0238)
- Claudius Witzler (ORCID: https://orcid.org/0009-0003-0903-4127)
- Thati Madhusudhan (ORCID: https://orcid.org/0000-0003-0631-8725)
- Kateryna Moiko (ORCID: https://orcid.org/0009-0000-9703-0705)
- Franziska Greulich (ORCID: https://orcid.org/0000-0001-8780-8528)
- Christine Espinola–Klein (ORCID: https://orcid.org/0000-0001-9243-1761)
- Cécile Derieux (ORCID: https://orcid.org/0000-0002-2743-4023)
- Beichen Sun (ORCID: https://orcid.org/0009-0009-4948-1494)
- Konstantinos Zifkos (ORCID: https://orcid.org/0000-0002-4878-1542)
- Iman Ghasemi (ORCID: https://orcid.org/0009-0008-4832-8757)
- Andreas Bock (ORCID: https://orcid.org/0000-0002-6344-6494)
- Payal Guliani (ORCID: https://orcid.org/0009-0007-6915-9131)
- Philipp Lurz
- Henriette N. Uhlenhaut
- Werner Schmitz
Institutions
- Johannes Gutenberg University Mainz (DE)
- University of Würzburg (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- German Centre for Cardiovascular Research (DE)
- German Center for Diabetes Research (DE)
- Technical University of Munich (DE)
Publication Details
- Journal
- Angiogenesis
- Published
- 2026-09-25
- DOI
- https://doi.org/10.1007/s10456-026-10096-y
- Primary Topic
- Angiogenesis and VEGF in Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00