Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction

Area of Science:

• Cardiovascular Biology
• Vascular Cell Biology
• Heart Failure Pathophysiology

Background:

• Microvascular dysfunction is implicated in heart failure with preserved ejection fraction (HFpEF).
• The initial molecular and cellular events driving HFpEF-related microvascular alterations remain unclear.
• Understanding these early events is crucial for developing effective HFpEF therapies.

Purpose of the Study:

• To investigate the temporal onset of microvascular alterations in HFpEF.
• To elucidate the role of pericyte dysfunction in HFpEF progression.
• To determine how pericyte dysfunction contributes to cardiac dysfunction.

Main Methods:

• Utilized the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at 6, 14, and 21 weeks.
• Assessed microvascular dysfunction, including inflammatory activation and endothelial barrier function.
• Studied a mouse model with reduced pericyte coverage (PDGF-B) and in vitro pericyte models under oxidative stress.

Main Results:

• Pericyte loss was the earliest microvascular change, preceding diastolic dysfunction.
• Obese ZSF1 rats showed reduced pericyte proliferation, altered morphology, and increased capillary diameter at 14 weeks.
• Reduced pericyte coverage in mice led to diastolic dysfunction; in vitro, oxidative stress impaired pericytes and induced endothelial inflammation.

Conclusions:

• Pericytes are critical for maintaining endothelial cell function and microvascular integrity.
• Loss of pericytes exacerbates endothelial inflammatory responses.
• Pericyte dysfunction promotes microvascular dysfunction, accelerating the development of HFpEF.