Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction.

Autor:	Simmonds SJ; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium., Grootaert MOJ; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium., Cuijpers I; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium.; Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands., Carai P; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium., Geuens N; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium., Herwig M; Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, Bochum 44801, Germany.; Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, St.Josef-Hospital, Ruhr University Bochum, Bochum, Germany., Baatsen P; VIB-KU Leuven, Center for Brain and Disease Research, Electron Microscopy Platform & VIB Bioimaging Core, Leuven, Belgium.; Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium., Hamdani N; Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, Bochum 44801, Germany.; Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, St.Josef-Hospital, Ruhr University Bochum, Bochum, Germany., Luttun A; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium., Heymans S; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium.; Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands., Jones EAV; Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, bus 911, Leuven 3000, Belgium.; Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands.
Jazyk:	angličtina
Zdroj:	European heart journal open [Eur Heart J Open] 2023 Dec 09; Vol. 4 (1), pp. oead129. Date of Electronic Publication: 2023 Dec 09 (Print Publication: 2024).
DOI:	10.1093/ehjopen/oead129
Abstrakt:	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 ( PDGF-B ret/ret ), which spontaneously developed many aspects of diastolic dysfunction. Pericytes exposed to oxidative stress in vitro 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. Competing Interests: Conflict of interest: None. (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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