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

Area of Science:

• Cardiovascular Research
• Metabolic Disease Research
• Vascular Biology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is linked to metabolic issues.
• Endothelial cell (EC) dysfunction is implicated in HFpEF, but mural cell roles are unknown.

Purpose of the Study:

• Investigate mural cell dysfunction in a novel HFpEF mouse model.
• Determine the contribution of mural cells to HFpEF pathophysiology.

Main Methods:

• Utilized a diabetic db/db mouse model with high salt intake.
• Employed single-cell RNA sequencing, NicheNet analysis, and histology.
• Labeled mural cells using genetic tools for detailed analysis.

Main Results:

• Diabetic mice developed diastolic dysfunction, capillary loss, and pericyte loss.
• EC dysfunction and increased pericyte-EC space were observed early.
• Mural cells, not ECs, strongly signaled to ECs, inducing growth arrest via TNFα.

Conclusions:

• Mural cell dysfunction is a key contributor to HFpEF.
• Mural cells induce coronary vessel remodeling by inhibiting EC proliferation and promoting inflammation.
• TNFα-dependent paracrine signaling from mural cells plays a critical role.