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Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis.

ABSTRACT: Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-? signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets.

SUBMITTER: Lin SL

PROVIDER: S-EPMC3070546 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis.

Lin Shuei-Liong SL Chang Fan-Chi FC Schrimpf Claudia C Chen Yi-Ting YT Wu Ching-Fang CF Wu Vin-Cent VC Chiang Wen-Chih WC Kuhnert Frank F Kuo Calvin J CJ Chen Yung-Ming YM Wu Kwan-Dun KD Tsai Tun-Jun TJ Duffield Jeremy S JS

The American journal of pathology 20110201 2

Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-β signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by ci ...[more]

PMID: 21281822

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Project description:Chronic kidney disease (CKD) is common in patients with heart failure and often results in left ventricular diastolic dysfunction (LVDD). However, the mechanisms responsible for cardiac damage in CKD-LVDD remain to be elucidated. Epigenetic alterations may impose long-lasting effects on cellular transcription and function, but their exact role in CKD-LVDD is unknown. We investigate whether changes in cardiac site-specific DNA methylation profiles might be implicated in cardiac abnormalities in CKD-LVDD. CKD-LVDD and normal control pigs (n = 6 each) were studied for 14 wk. Renal and cardiac hemodynamics were quantified by multidetector CT and echocardiography. In randomly selected pigs (n = 3/group), cardiac site-specific 5-methylcytosine (5mC) immunoprecipitation (MeDIP)- and mRNA-sequencing (seq) were performed, followed by integrated (MeDiP-seq/mRNA-seq analysis), and confirmatory ex vivo studies. MeDIP-seq analysis revealed 261 genes with higher (fold change > 1.4; P < 0.05) and 162 genes with lower (fold change < 0.7; P < 0.05) 5mC levels in CKD-LVDD versus normal pigs, which were primarily implicated in vascular endothelial growth factor (VEGF)-related signaling and angiogenesis. Integrated MeDiP-seq/mRNA-seq analysis identified a select group of VEGF-related genes in which 5mC levels were higher, but mRNA expression was lower in CKD-LVDD versus normal pigs. Cardiac VEGF signaling gene and VEGF protein expression were blunted in CKD-LVDD compared with controls and were associated with decreased subendocardial microvascular density. Cardiac epigenetic changes in VEGF-related genes are associated with impaired angiogenesis and cardiac microvascular rarefaction in swine CKD-LVDD. These observations may assist in developing novel therapies to ameliorate cardiac damage in CKD-LVDD.NEW & NOTEWORTHY Chronic kidney disease (CKD) often leads to left ventricular diastolic dysfunction (LVDD) and heart failure. Using a novel translational swine model of CKD-LVDD, we characterize the cardiac epigenetic landscape, identifying site-specific 5-methylcytosine changes in vascular endothelial growth factor (VEGF)-related genes associated with impaired angiogenesis and cardiac microvascular rarefaction. These observations shed light on the mechanisms of cardiac microvascular damage in CKD-LVDD and may assist in developing novel therapies for these patients.

Project description:Background and objectivesAnimal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function.Design, setting, participants, & measurementsThis observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes.ResultsPost-transplant biopsies were performed at a median of 113 days (interquartile range, 101-128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, -3.7%; interquartile range, -6.6% to -0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, -4.5%; interquartile range, -8.0% to -0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, -2.9%; 95% confidence interval, -4.0 to -1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation.ConclusionsPerioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.

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Dataset Information

Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis.

Publications

Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis.

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