Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling

• DOI: 10.1186/s12933-025-02623-w
• Publication Date: 2025-02-07T13:52:16Z
• Authors: Mandy O. J. Groot...; Alessandra Pasut; Jana Raman; Steven J. Simmonds; Bram Callewaert; Ümare Col; Mieke Dewerchin; Peter Carmeliet; Stephane Heymans; Elizabeth A. V. J...
• Keywords: Angiology; Endothelial Dysfunction; Cardiac Dysfunction

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular disease associated metabolic comorbidities. Microvascular dysfunction has been proposed to drive HFpEF, likely via endothelial cell (EC) dysfunction, yet the role of mural cells herein never explored. We used diabetic db/db mouse given 1% salt as new model HFpEF and crossed then PDGFRβtg/tg-CreERT2-EYFPtg/tg mice label cells. combined single-cell RNA sequencing, NichetNet analysis histology determine in HFpEF. Db/db for 8 weeks developed diastolic preceded by capillary density loss, pericyte loss vessel regression. At 4 salt, hearts already showed EC an anti-angiogenic signature, increase pericyte-EC intracellular space. + were further characterised increased ACTA2 expression, arteriole wall thickening enlargement. NicheNet on single transcriptomic data revealed little signalling from ECs cells; instead, signalled strongly ECs. Mechanistically, induces growth arrest TNFα-dependent paracrine downstream through STAT1. Mural contributes inducing coronary remodelling, at least part reducing proliferation inflammation signalling.