STAT3 expression is reduced in cardiac pericytes in HFpEF and its loss reduces cellular adhesion and induces pericyte senescence

TL;DR

Reduced STAT3 in cardiac pericytes contributes to heart failure with preserved ejection fraction by causing cell senescence and impaired adhesion.

Contribution

Identifies reduced STAT3 as a novel driver of pericyte dysfunction in HFpEF through in vitro and sequencing studies.

Findings

STAT3 expression is reduced in cardiac pericytes in HFpEF.

Loss of STAT3 induces pericyte senescence and impairs cellular adhesion.

STAT3 reduction activates a pro-fibrotic gene program in pericytes.

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure cases and is characterised by reduced pericyte coverage. While the contributions of other cardiac cell types to HFpEF are well‐studied, the role of pericytes remains less understood. Using murine single‐nucleus RNA‐sequencing to study cardiac pericytes in HFpEF, we identified reduced STAT3 expression as a hallmark of HFpEF pericytes. Mechanistic studies in vitro revealed that STAT3 deletion induces cellular senescence and impairs pericyte adhesion, recapitulating HFpEF‐like characteristics. These findings suggest that STAT3 is crucial for maintaining pericyte homeostasis and highlight its reduction as a potential driver of pericyte loss, a defining feature of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) accounts for half of the heart failure cases. It is characterised by microvascular dysfunction, associated with reduced pericyte coverage and diminished STAT3 expression in pericytes. Loss of STAT3 impairs pericyte adhesion, promotes senescence, and activates a pro‐fibrotic gene program. Our findings provide evidence that STAT3 is essential for sustaining pericyte function in HFpEF.

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