S. Simmonds, Mandy OJ Grootaert, I. Cuijpers, P. Carai, Nadéche Geuens, M. Herwig, Pieter Baatsen, Nazha Hamdani, A. Luttun, Stephane Heymans, E. A. Jones
{"title":"在舒张功能障碍的发展过程中,微血管功能障碍的始作俑者是毛细血管的损失","authors":"S. Simmonds, Mandy OJ Grootaert, I. Cuijpers, P. Carai, Nadéche Geuens, M. Herwig, Pieter Baatsen, Nazha Hamdani, A. Luttun, Stephane Heymans, E. A. Jones","doi":"10.1093/ehjopen/oead129","DOIUrl":null,"url":null,"abstract":"\n \n \n 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.\n \n \n \n Microvascular dysfunction, characterised 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-Bret/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.\n \n \n \n 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.\n","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":"1 9","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction\",\"authors\":\"S. Simmonds, Mandy OJ Grootaert, I. Cuijpers, P. Carai, Nadéche Geuens, M. Herwig, Pieter Baatsen, Nazha Hamdani, A. Luttun, Stephane Heymans, E. A. Jones\",\"doi\":\"10.1093/ehjopen/oead129\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"\\n \\n \\n 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.\\n \\n \\n \\n Microvascular dysfunction, characterised 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-Bret/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.\\n \\n \\n \\n 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.\\n\",\"PeriodicalId\":93995,\"journal\":{\"name\":\"European heart journal open\",\"volume\":\"1 9\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-12-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European heart journal open\",\"FirstCategoryId\":\"0\",\"ListUrlMain\":\"https://doi.org/10.1093/ehjopen/oead129\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European heart journal open","FirstCategoryId":"0","ListUrlMain":"https://doi.org/10.1093/ehjopen/oead129","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction
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.
Microvascular dysfunction, characterised 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-Bret/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.
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.