TY - JOUR
T1 - Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction
AU - Simmonds, Steven J
AU - Grootaert, Mandy O J
AU - Cuijpers, Ilona
AU - Carai, Paolo
AU - Geuens, Nadeche
AU - Herwig, Melissa
AU - Baatsen, Pieter
AU - Hamdani, Nazha
AU - Luttun, Aernout
AU - Heymans, Stephane
AU - Jones, Elizabeth A V
PY - 2024/1
Y1 - 2024/1
N2 - AIMS: Microvascular dysfunction has been proposed to drive heart failure with preserved ejection fraction (HFpEF), but the initiating molecular and cellular events are largely unknown. Our objective was to determine when microvascular alterations in HFpEF begin, how they contribute to disease progression, and how pericyte dysfunction plays a role herein. METHODS AND RESULTS: Microvascular dysfunction, characterized by inflammatory activation, loss of junctional barrier function, and altered pericyte-endothelial crosstalk, was assessed with respect to the development of cardiac dysfunction, in the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at three time points: 6, 14, and 21 weeks of age. Pericyte loss was the earliest and strongest microvascular change, occurring before prominent echocardiographic signs of diastolic dysfunction were present. Pericytes were shown to be less proliferative and had a disrupted morphology at 14 weeks in the obese ZSF1 animals, who also exhibited an increased capillary luminal diameter and disrupted endothelial junctions. Microvascular dysfunction was also studied in a mouse model of chronic reduction in capillary pericyte coverage ( ), which spontaneously developed many aspects of diastolic dysfunction. Pericytes exposed to oxidative stress showed downregulation of cell cycle-associated pathways and induced a pro-inflammatory state in endothelial cells upon co-culture. CONCLUSION: We propose pericytes are important for maintaining endothelial cell function, where loss of pericytes enhances the reactivity of endothelial cells to inflammatory signals and promotes microvascular dysfunction, thereby accelerating the development of HFpEF.
AB - AIMS: Microvascular dysfunction has been proposed to drive heart failure with preserved ejection fraction (HFpEF), but the initiating molecular and cellular events are largely unknown. Our objective was to determine when microvascular alterations in HFpEF begin, how they contribute to disease progression, and how pericyte dysfunction plays a role herein. METHODS AND RESULTS: Microvascular dysfunction, characterized by inflammatory activation, loss of junctional barrier function, and altered pericyte-endothelial crosstalk, was assessed with respect to the development of cardiac dysfunction, in the Zucker fatty and spontaneously hypertensive (ZSF1) obese rat model of HFpEF at three time points: 6, 14, and 21 weeks of age. Pericyte loss was the earliest and strongest microvascular change, occurring before prominent echocardiographic signs of diastolic dysfunction were present. Pericytes were shown to be less proliferative and had a disrupted morphology at 14 weeks in the obese ZSF1 animals, who also exhibited an increased capillary luminal diameter and disrupted endothelial junctions. Microvascular dysfunction was also studied in a mouse model of chronic reduction in capillary pericyte coverage ( ), which spontaneously developed many aspects of diastolic dysfunction. Pericytes exposed to oxidative stress showed downregulation of cell cycle-associated pathways and induced a pro-inflammatory state in endothelial cells upon co-culture. CONCLUSION: We propose pericytes are important for maintaining endothelial cell function, where loss of pericytes enhances the reactivity of endothelial cells to inflammatory signals and promotes microvascular dysfunction, thereby accelerating the development of HFpEF.
KW - HFpEF
KW - Metabolic comorbidities
KW - Microvascular dysfunction
KW - Pericytes
U2 - 10.1093/ehjopen/oead129
DO - 10.1093/ehjopen/oead129
M3 - Article
SN - 2752-4191
VL - 4
JO - European heart journal open
JF - European heart journal open
IS - 1
M1 - oead129
ER -