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

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