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Blood vessels are continuously exposed to hemodynamic forces due to the pulsatile nature of the blood flow. In normal physiological settings, these forces are essential in the maintenance of vascular cell function and structure, vascular growth, and in the regulation of vascular tone. However, when exceeding the physiological range these biomechanical forces become detrimental and may initiate pathological pathways. In this chapter, we discuss the types of vascular biomechanical forces, unravel cellular and molecular mechanisms underlying the physiological and pathophysiological response of the vascular cells to these biomechanical stimuli, and describe their role in triggering vascular growth.
Ranganath Maringanti; Elana Meijer; Maarten M. Brandt; Dirk J. Duncker; Caroline Cheng. Contributions of Wall Stretch and Shear Stress to Vascular Regulation: Molecular Mechanisms of Homeostasis and Expansion. Non-coding RNAs in the Vasculature 2021, 21 -46.
AMA StyleRanganath Maringanti, Elana Meijer, Maarten M. Brandt, Dirk J. Duncker, Caroline Cheng. Contributions of Wall Stretch and Shear Stress to Vascular Regulation: Molecular Mechanisms of Homeostasis and Expansion. Non-coding RNAs in the Vasculature. 2021; ():21-46.
Chicago/Turabian StyleRanganath Maringanti; Elana Meijer; Maarten M. Brandt; Dirk J. Duncker; Caroline Cheng. 2021. "Contributions of Wall Stretch and Shear Stress to Vascular Regulation: Molecular Mechanisms of Homeostasis and Expansion." Non-coding RNAs in the Vasculature , no. : 21-46.
For the survival and integration of complex large-sized tissue engineered (TE) organ constructs that exceed the maximal nutrients and oxygen diffusion distance required for cell survival, graft (pre-)vascularization to ensure medium or blood supply is crucial. To achieve this, the morphology and functionality of the micro-capillary bed should be mimicked by incorporating vascular cell populations including endothelium and mural cells. Pericytes play a crucial role in microvascular function, blood vessel stability, angiogenesis and blood pressure regulation. In addition, tissue-specific pericytes are important in maintaining specific functions in different organs, including vitamin A storage in the liver, renin production in the kidneys and maintenance of the Blood-Brain-Barrier (BBB). Together with their multipotential differentiation capacity, this makes pericytes the preferred cell type for application in TE grafts. The use of a tissue-specific pericyte cell population that matches the TE organ may benefit organ function. In this review we provide an overview of the literature for graft (pre)-vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts.
Miss Elana Marianne Meijer; Christian G.M. Van Dijk; Rafael Kramann; Marianne C. Verhaar; Caroline Cheng. Implementation of Pericytes in Vascular Regeneration Strategies. Tissue Engineering Part B: Reviews 2021, 1 .
AMA StyleMiss Elana Marianne Meijer, Christian G.M. Van Dijk, Rafael Kramann, Marianne C. Verhaar, Caroline Cheng. Implementation of Pericytes in Vascular Regeneration Strategies. Tissue Engineering Part B: Reviews. 2021; ():1.
Chicago/Turabian StyleMiss Elana Marianne Meijer; Christian G.M. Van Dijk; Rafael Kramann; Marianne C. Verhaar; Caroline Cheng. 2021. "Implementation of Pericytes in Vascular Regeneration Strategies." Tissue Engineering Part B: Reviews , no. : 1.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are pivotal regulators of extracellular matrix (ECM) composition and could, due to their dynamic activity, function as prognostic tools for fibrosis and cardiac function in left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). We conducted a systematic review on experimental animal models of LVDD and HFpEF published in MEDLINE or Embase. Twenty-three studies were included with a total of 36 comparisons that reported established LVDD, quantification of cardiac fibrosis and cardiac MMP or TIMP expression or activity. LVDD/HFpEF models were divided based on underlying pathology: hemodynamic overload (17 comparisons), metabolic alteration (16 comparisons) or ageing (3 comparisons). Meta-analysis showed that echocardiographic parameters were not consistently altered in LVDD/HFpEF with invasive hemodynamic measurements better representing LVDD. Increased myocardial fibrotic area indicated comparable characteristics between hemodynamic and metabolic models. Regarding MMPs and TIMPs; MMP2 and MMP9 activity and protein and TIMP1 protein levels were mainly enhanced in hemodynamic models. In most cases only mRNA was assessed and there were no correlations between cardiac tissue and plasma levels. Female gender, a known risk factor for LVDD and HFpEF, was underrepresented. Novel studies should detail relevant model characteristics and focus on MMP and TIMP protein expression and activity to identify predictive circulating markers in cardiac ECM remodeling.
Merle M. Krebber; Christian G. M. Van Dijk; Robin W. M. Vernooij; Maarten M. Brandt; Craig A. Emter; Christoph D. Rau; Joost O. Fledderus; Dirk J. Duncker; Marianne C. Verhaar; Caroline Cheng; Jaap A. Joles. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences 2020, 21, 6742 .
AMA StyleMerle M. Krebber, Christian G. M. Van Dijk, Robin W. M. Vernooij, Maarten M. Brandt, Craig A. Emter, Christoph D. Rau, Joost O. Fledderus, Dirk J. Duncker, Marianne C. Verhaar, Caroline Cheng, Jaap A. Joles. Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences. 2020; 21 (18):6742.
Chicago/Turabian StyleMerle M. Krebber; Christian G. M. Van Dijk; Robin W. M. Vernooij; Maarten M. Brandt; Craig A. Emter; Christoph D. Rau; Joost O. Fledderus; Dirk J. Duncker; Marianne C. Verhaar; Caroline Cheng; Jaap A. Joles. 2020. "Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis." International Journal of Molecular Sciences 21, no. 18: 6742.
Background H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes. Results We detected chromatin regions with differential acetylation activity (DARs; P adj. < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls. Conclusions Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles, we further provide promising TF-encoding genes that could serve as master regulators of myocardial remodeling. Combined, our findings highlight the important role of chromatin regulatory signatures in understanding disease etiology.
Jiayi Pei; Magdalena Harakalova; Thomas Treibel; R Thomas Lumbers; Bastiaan J. Boukens; Igor R. Efimov; Jip T. Van Dinter; Arantxa González; Begoña López; Hamid El Azzouzi; Noortje Van Den Dungen; Christian G. M. Van Dijk; Merle M. Krebber; Hester M. Den Ruijter; Gerard Pasterkamp; Dirk J. Duncker; Edward E. S. Nieuwenhuis; Roel De Weger; Manon M. Huibers; Aryan Vink; Jason H. Moore; James Moon; Marianne C. Verhaar; Georgios Kararigas; Michal Mokry; Folkert W. Asselbergs; Caroline Cheng. H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts. Clinical Epigenetics 2020, 12, 1 -18.
AMA StyleJiayi Pei, Magdalena Harakalova, Thomas Treibel, R Thomas Lumbers, Bastiaan J. Boukens, Igor R. Efimov, Jip T. Van Dinter, Arantxa González, Begoña López, Hamid El Azzouzi, Noortje Van Den Dungen, Christian G. M. Van Dijk, Merle M. Krebber, Hester M. Den Ruijter, Gerard Pasterkamp, Dirk J. Duncker, Edward E. S. Nieuwenhuis, Roel De Weger, Manon M. Huibers, Aryan Vink, Jason H. Moore, James Moon, Marianne C. Verhaar, Georgios Kararigas, Michal Mokry, Folkert W. Asselbergs, Caroline Cheng. H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts. Clinical Epigenetics. 2020; 12 (1):1-18.
Chicago/Turabian StyleJiayi Pei; Magdalena Harakalova; Thomas Treibel; R Thomas Lumbers; Bastiaan J. Boukens; Igor R. Efimov; Jip T. Van Dinter; Arantxa González; Begoña López; Hamid El Azzouzi; Noortje Van Den Dungen; Christian G. M. Van Dijk; Merle M. Krebber; Hester M. Den Ruijter; Gerard Pasterkamp; Dirk J. Duncker; Edward E. S. Nieuwenhuis; Roel De Weger; Manon M. Huibers; Aryan Vink; Jason H. Moore; James Moon; Marianne C. Verhaar; Georgios Kararigas; Michal Mokry; Folkert W. Asselbergs; Caroline Cheng. 2020. "H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts." Clinical Epigenetics 12, no. 1: 1-18.
In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell–matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue; however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic ECM proteins EMILIN1 and FBN1 are significantly enriched in fetal renal arteries and are mainly produced by cells of mesenchymal origin. We functionally tested the role of EMILIN1 and FBN1 by anchoring the ECM secreted by vascular smooth muscle cells (SMCs) to glass coverslips. This ECM layer was depleted from either EMILIN1 or FBN1 by using siRNA targeting of the SMCs. Cultured endothelial cells (ECs) on this modified ECM layer showed alterations on the transcriptome level of multiple pathways, especially the Rho GTPase controlled pathways. However, no significant alterations in adhesion, migration or proliferation were observed when ECs were cultured on EMILIN1- or FNB1-deficient ECM. To conclude, the proteome analysis identified unique ECM proteins involved in the embryonic development of renal arteries. Alterations in transcriptome levels of ECs cultured on EMILIN1- or FBN1-deficient ECM showed that these candidate proteins could affect the endothelial (regenerative) response.
Christian G.M. Van Dijk; Laura Louzao Martinez; Elise Van Mulligen; Bart Boermans; Jeroen A.A. Demmers; Thierry P.P. Van Den Bosch; Marie-José Goumans; Dirk J. Duncker; Marianne C. Verhaar; Caroline Cheng. Extracellular Matrix Analysis of Human Renal Arteries in Both Quiescent and Active Vascular State. International Journal of Molecular Sciences 2020, 21, 3905 .
AMA StyleChristian G.M. Van Dijk, Laura Louzao Martinez, Elise Van Mulligen, Bart Boermans, Jeroen A.A. Demmers, Thierry P.P. Van Den Bosch, Marie-José Goumans, Dirk J. Duncker, Marianne C. Verhaar, Caroline Cheng. Extracellular Matrix Analysis of Human Renal Arteries in Both Quiescent and Active Vascular State. International Journal of Molecular Sciences. 2020; 21 (11):3905.
Chicago/Turabian StyleChristian G.M. Van Dijk; Laura Louzao Martinez; Elise Van Mulligen; Bart Boermans; Jeroen A.A. Demmers; Thierry P.P. Van Den Bosch; Marie-José Goumans; Dirk J. Duncker; Marianne C. Verhaar; Caroline Cheng. 2020. "Extracellular Matrix Analysis of Human Renal Arteries in Both Quiescent and Active Vascular State." International Journal of Molecular Sciences 21, no. 11: 3905.
A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel–Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl−/− mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.
Zhiyong Lei; Timothy D. Klasson; Maarten M. Brandt; Glenn Van De Hoek; Ive Logister; Caroline Cheng; Pieter A. Doevendans; Joost P. G. Sluijter; Rachel H. Giles. Control of Angiogenesis via a VHL/miR-212/132 Axis. Cells 2020, 9, 1017 .
AMA StyleZhiyong Lei, Timothy D. Klasson, Maarten M. Brandt, Glenn Van De Hoek, Ive Logister, Caroline Cheng, Pieter A. Doevendans, Joost P. G. Sluijter, Rachel H. Giles. Control of Angiogenesis via a VHL/miR-212/132 Axis. Cells. 2020; 9 (4):1017.
Chicago/Turabian StyleZhiyong Lei; Timothy D. Klasson; Maarten M. Brandt; Glenn Van De Hoek; Ive Logister; Caroline Cheng; Pieter A. Doevendans; Joost P. G. Sluijter; Rachel H. Giles. 2020. "Control of Angiogenesis via a VHL/miR-212/132 Axis." Cells 9, no. 4: 1017.
We present a microfluidic vascular device. Vascular cells in a 3D-ECM environment support hemodynamic flow and enable monocyte interaction.
Christian Gerardus Marinus Van Dijk; Maarten M. Brandt; Nikolaos Poulis; Jonas Anten; Matthijs Van Der Moolen; Liana Kramer; Erik F. G. A. Homburg; Laura Louzao-Martinez; Jiayi Pei; Merle M. Krebber; Bas W. M. Van Balkom; Petra De Graaf; Dirk J. Duncker; Marianne C. Verhaar; Regina Luttge; Caroline Cheng. A new microfluidic model that allows monitoring of complex vascular structures and cell interactions in a 3D biological matrix. Lab on a Chip 2020, 20, 1827 -1844.
AMA StyleChristian Gerardus Marinus Van Dijk, Maarten M. Brandt, Nikolaos Poulis, Jonas Anten, Matthijs Van Der Moolen, Liana Kramer, Erik F. G. A. Homburg, Laura Louzao-Martinez, Jiayi Pei, Merle M. Krebber, Bas W. M. Van Balkom, Petra De Graaf, Dirk J. Duncker, Marianne C. Verhaar, Regina Luttge, Caroline Cheng. A new microfluidic model that allows monitoring of complex vascular structures and cell interactions in a 3D biological matrix. Lab on a Chip. 2020; 20 (10):1827-1844.
Chicago/Turabian StyleChristian Gerardus Marinus Van Dijk; Maarten M. Brandt; Nikolaos Poulis; Jonas Anten; Matthijs Van Der Moolen; Liana Kramer; Erik F. G. A. Homburg; Laura Louzao-Martinez; Jiayi Pei; Merle M. Krebber; Bas W. M. Van Balkom; Petra De Graaf; Dirk J. Duncker; Marianne C. Verhaar; Regina Luttge; Caroline Cheng. 2020. "A new microfluidic model that allows monitoring of complex vascular structures and cell interactions in a 3D biological matrix." Lab on a Chip 20, no. 10: 1827-1844.
Microvascular homeostasis is strictly regulated, requiring close interaction between endothelial cells and pericytes. Here, we aimed to improve our understanding of how microvascular crosstalk affects pericytes. Human-derived pericytes, cultured in absence, or presence of human endothelial cells, were studied by RNA sequencing. Compared with mono-cultured pericytes, a total of 6704 genes were differentially expressed in co-cultured pericytes. Direct endothelial contact induced transcriptome profiles associated with pericyte maturation, suppression of extracellular matrix production, proliferation, and morphological adaptation. In vitro studies confirmed enhanced pericyte proliferation mediated by endothelial-derived PDGFB and pericyte-derived HB-EGF and FGF2. Endothelial-induced PLXNA2 and ACTR3 upregulation also triggered pericyte morphological adaptation. Pathway analysis predicted a key role for TGFβ signaling in endothelial-induced pericyte differentiation, whereas the effect of signaling via gap- and adherens junctions was limited. We demonstrate that endothelial cells have a major impact on the transcriptional profile of pericytes, regulating endothelial-induced maturation, proliferation, and suppression of ECM production.
Maarten M. Brandt; Christian G. M. Van Dijk; Ranganath Maringanti; Ihsan Chrifi; Rafael Kramann; Marianne C. Verhaar; Dirk J. Duncker; Michal Mokry; Caroline Cheng. Transcriptome analysis reveals microvascular endothelial cell-dependent pericyte differentiation. Scientific Reports 2019, 9, 1 -12.
AMA StyleMaarten M. Brandt, Christian G. M. Van Dijk, Ranganath Maringanti, Ihsan Chrifi, Rafael Kramann, Marianne C. Verhaar, Dirk J. Duncker, Michal Mokry, Caroline Cheng. Transcriptome analysis reveals microvascular endothelial cell-dependent pericyte differentiation. Scientific Reports. 2019; 9 (1):1-12.
Chicago/Turabian StyleMaarten M. Brandt; Christian G. M. Van Dijk; Ranganath Maringanti; Ihsan Chrifi; Rafael Kramann; Marianne C. Verhaar; Dirk J. Duncker; Michal Mokry; Caroline Cheng. 2019. "Transcriptome analysis reveals microvascular endothelial cell-dependent pericyte differentiation." Scientific Reports 9, no. 1: 1-12.
Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in human umbilical vein endothelial cells (HUVECs) after IS or control medium treatment and identified 1293 genes that were affected in a IS-induced response. Gene enrichment analysis highlighted pathways involved in altered vascular formation and cell metabolism. We confirmed these transcriptome profiles at the functional level by demonstrating decreased viability and increased cell senescence in response to IS treatment. In line with the additional pathways highlighted by the transcriptome analysis, we further could demonstrate that IS exposure of HUVECs promoted tubule formation as shown by the increase in total tubule length in a 3D HUVECs/pericytes co-culture assay. Notably, the pro-angiogenic response of IS and increased ROS production were abolished when CYP1B1, one of the main target genes that was highly upregulated by IS, was silenced. This observation indicates IS-induced ROS in endothelial cells is CYP1B1-dependent. Taken together, our findings demonstrate that IS promotes angiogenesis and CYP1B1 is an important factor in IS-activated angiogenic response.
Jiayi Pei; Rio Juni; Magdalena Harakalova; Dirk J. Duncker; Folkert W. Asselbergs; Pieter Koolwijk; Victor Van Hinsbergh; Marianne C. Verhaar; Michal Mokry; Caroline Cheng; Pei; Juni; Hinsbergh. Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1. Toxins 2019, 11, 454 .
AMA StyleJiayi Pei, Rio Juni, Magdalena Harakalova, Dirk J. Duncker, Folkert W. Asselbergs, Pieter Koolwijk, Victor Van Hinsbergh, Marianne C. Verhaar, Michal Mokry, Caroline Cheng, Pei, Juni, Hinsbergh. Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1. Toxins. 2019; 11 (8):454.
Chicago/Turabian StyleJiayi Pei; Rio Juni; Magdalena Harakalova; Dirk J. Duncker; Folkert W. Asselbergs; Pieter Koolwijk; Victor Van Hinsbergh; Marianne C. Verhaar; Michal Mokry; Caroline Cheng; Pei; Juni; Hinsbergh. 2019. "Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1." Toxins 11, no. 8: 454.
Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction. To clarify if and how interaction between these comorbidities contributes to development of diastolic dysfunction, lean and obese ZSF1 rats were treated with deoxycorticosterone acetate implants and a high‐salt diet (DS) to induce severe hypertension, or with placebo. In addition to echocardiographic, metabolic and hemodynamic analyses, immunohistochemistry and RNAseq were performed on left ventricular tissue. Obesity negatively affected cardiac output, led to an elevated E/e’ ratio and mildly reduced ejection fraction. DS‐induced hypertension did not affect cardiac output and minimally elevated E/e’ ratio. Diastolic derangements in placebo‐treated obese rats developed in absence of inflammation and fibrosis, yet in presence of oxidative stress and hypertrophic remodelling. In contrast, hypertension triggered apoptosis, inflammation and fibrosis, with limited synergy of the comorbidities observed for inflammation and fibrosis. Transcriptional data suggested that these comorbidities exerted opposite effects on mitochondrial function. In placebo‐treated obese rats, genes involved in fatty acid metabolism were up‐regulated, whereas DS‐induced a down‐regulation of genes involved in oxidative phosphorylation. Overall, limited interaction was observed between these comorbidities in development of diastolic dysfunction. Importantly, differences in obesity‐ and hypertension‐induced cardiac remodelling emphasize the necessity for comorbidity‐specific phenotypical characterization.
Maarten M. Brandt; Isabel T. N. Nguyen; Merle M. Krebber; Jens Van De Wouw; Michal Mokry; Maarten J. Cramer; Dirk J. Duncker; Marianne C. Verhaar; Jaap A. Joles; Caroline Cheng. Limited synergy of obesity and hypertension, prevalent risk factors in onset and progression of heart failure with preserved ejection fraction. Journal of Cellular and Molecular Medicine 2019, 23, 6666 -6678.
AMA StyleMaarten M. Brandt, Isabel T. N. Nguyen, Merle M. Krebber, Jens Van De Wouw, Michal Mokry, Maarten J. Cramer, Dirk J. Duncker, Marianne C. Verhaar, Jaap A. Joles, Caroline Cheng. Limited synergy of obesity and hypertension, prevalent risk factors in onset and progression of heart failure with preserved ejection fraction. Journal of Cellular and Molecular Medicine. 2019; 23 (10):6666-6678.
Chicago/Turabian StyleMaarten M. Brandt; Isabel T. N. Nguyen; Merle M. Krebber; Jens Van De Wouw; Michal Mokry; Maarten J. Cramer; Dirk J. Duncker; Marianne C. Verhaar; Jaap A. Joles; Caroline Cheng. 2019. "Limited synergy of obesity and hypertension, prevalent risk factors in onset and progression of heart failure with preserved ejection fraction." Journal of Cellular and Molecular Medicine 23, no. 10: 6666-6678.
Cell-based approaches using tissue engineering and regenerative medicine to replace damaged renal tissue with 3D constructs is a promising emerging therapy for kidney disease. Besides living cells, a template provided by a scaffold based on biomaterials and bioactive factors is needed for successful kidney engineering. Nature's own template for a scaffolding system is the extracellular matrix (ECM). Research has focused on mapping the mature renal ECM; however, the developing fetal ECM matches more the active environment required in 3D renal constructs. Here, we characterized the differences between the human fetal and mature renal ECM using spectrometry-based proteomics of decellularized tissue. We identified 99 different renal ECM proteins of which the majority forms an overlapping core, but also includes proteins enriched in either the fetal or mature ECM. Relative protein quantification showed a significant dominance of EMILIN1 in the fetal ECM. We functionally tested the role of EMILIN1 in the ECM using a novel methodology that permits the reliable anchorage of native cell-secreted ECM to glass coverslips. Depletion of EMILIN1 from the ECM layer using siRNA mediated knock-down technologies does not affect renal epithelial cell growth, but does promote migration. Lack of EMILIN1 in the ECM layer reduces the adhesion strength of renal epithelial cells, shown by a decrease in focal adhesion points and associated stress fibers. We showed in this study the importance of a human renal fetal and mature ECM catalogue for identifying promising ECM components that have high implementation potential in scaffolds for 3D renal constructs.
Laura Louzao-Martinez; Christian G.M. van Dijk; Yan Juan Xu; Amber Korn; Nicolaas J. Bekker; Romi Brouwhuis; Maria Novella Nicese; Jeroen A.A. Demmers; Marie-José T.H. Goumans; Rosalinde Masereeuw; Dirk J. Duncker; Marianne C. Verhaar; Caroline Cheng. A proteome comparison between human fetal and mature renal extracellular matrix identifies EMILIN1 as a regulator of renal epithelial cell adhesion. Matrix Biology Plus 2019, 4, 100011 .
AMA StyleLaura Louzao-Martinez, Christian G.M. van Dijk, Yan Juan Xu, Amber Korn, Nicolaas J. Bekker, Romi Brouwhuis, Maria Novella Nicese, Jeroen A.A. Demmers, Marie-José T.H. Goumans, Rosalinde Masereeuw, Dirk J. Duncker, Marianne C. Verhaar, Caroline Cheng. A proteome comparison between human fetal and mature renal extracellular matrix identifies EMILIN1 as a regulator of renal epithelial cell adhesion. Matrix Biology Plus. 2019; 4 ():100011.
Chicago/Turabian StyleLaura Louzao-Martinez; Christian G.M. van Dijk; Yan Juan Xu; Amber Korn; Nicolaas J. Bekker; Romi Brouwhuis; Maria Novella Nicese; Jeroen A.A. Demmers; Marie-José T.H. Goumans; Rosalinde Masereeuw; Dirk J. Duncker; Marianne C. Verhaar; Caroline Cheng. 2019. "A proteome comparison between human fetal and mature renal extracellular matrix identifies EMILIN1 as a regulator of renal epithelial cell adhesion." Matrix Biology Plus 4, no. : 100011.
Formation of a functional vascular system is essential and its formation is a highly regulated process initiated during embryogenesis, which continues to play important roles throughout life in both health and disease. In previous studies, Fzd5 was shown to be critically involved in this process and here we investigated the molecular mechanism by which endothelial loss of this receptor attenuates angiogenesis. Using short interference RNA-mediated loss-of-function assays, the function and mechanism of signaling via Fzd5 was studied in human endothelial cells (ECs). Our findings indicate that Fzd5 signaling promotes neovessel formation in vitro in a collagen matrix-based 3D co-culture of primary vascular cells. Silencing of Fzd5 reduced EC proliferation, as a result of G0/G1 cell cycle arrest, and decreased cell migration. Furthermore, Fzd5 knockdown resulted in enhanced expression of the factors Angpt2 and Flt1, which are mainly known for their destabilizing effects on the vasculature. In Fzd5-silenced ECs, Angpt2 and Flt1 upregulation was induced by enhanced PKC signaling, without the involvement of canonical Wnt signaling, non-canonical Wnt/Ca2+-mediated activation of NFAT, and non-canonical Wnt/PCP-mediated activation of JNK. We demonstrated that PKC-induced transcription of Angpt2 and Flt1 involved the transcription factor Ets1. The current study demonstrates a pro-angiogenic role of Fzd5, which was shown to be involved in endothelial tubule formation, cell cycle progression and migration, and partly does so by repression of PKC/Ets1-mediated transcription of Flt1 and Angpt2.
Maarten M. Brandt; Christian G. M. Van Dijk; Ihsan Chrifi; Heleen M. Kool; Petra E. Bürgisser; Laura Louzao Martinez; Jiayi Pei; Robbert J. Rottier; Marianne Verhaar; Dirk J. Duncker; Caroline Cheng. Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1. Angiogenesis 2018, 21, 805 -821.
AMA StyleMaarten M. Brandt, Christian G. M. Van Dijk, Ihsan Chrifi, Heleen M. Kool, Petra E. Bürgisser, Laura Louzao Martinez, Jiayi Pei, Robbert J. Rottier, Marianne Verhaar, Dirk J. Duncker, Caroline Cheng. Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1. Angiogenesis. 2018; 21 (4):805-821.
Chicago/Turabian StyleMaarten M. Brandt; Christian G. M. Van Dijk; Ihsan Chrifi; Heleen M. Kool; Petra E. Bürgisser; Laura Louzao Martinez; Jiayi Pei; Robbert J. Rottier; Marianne Verhaar; Dirk J. Duncker; Caroline Cheng. 2018. "Endothelial loss of Fzd5 stimulates PKC/Ets1-mediated transcription of Angpt2 and Flt1." Angiogenesis 21, no. 4: 805-821.
Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chromosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis. Expression quantitative trait loci analysis revealed that mRNA levels of many target genes are genotype dependent. Pathway analyses showed that target genes were enriched in processes crucial for renal function, identifying dysregulated geranylgeranyl diphosphate biosynthesis as a potential disease mechanism. Overall, our data annotated multiple genes to previously reported CKD-associated single-nucleotide polymorphisms and provided evidence for interaction between these loci and target genes. This pipeline provides a novel technique for hypothesis generation and complements classic GWAS interpretation. Future studies are required to specify the implications of our dataset and further reveal the complex roles that common variants have in complex diseases, such as CKD.
Maarten M. Brandt; Claartje A. Meddens; Laura Louzao Martinez; Noortje A.M. Van Den Dungen; Nico R. Lansu; Edward E.S. Nieuwenhuis; Dirk J. Duncker; Marianne C. Verhaar; Jaap A. Joles; Michal Mokry; Caroline Cheng. Chromatin Conformation Links Distal Target Genes to CKD Loci. Journal of the American Society of Nephrology 2017, 29, 462 -476.
AMA StyleMaarten M. Brandt, Claartje A. Meddens, Laura Louzao Martinez, Noortje A.M. Van Den Dungen, Nico R. Lansu, Edward E.S. Nieuwenhuis, Dirk J. Duncker, Marianne C. Verhaar, Jaap A. Joles, Michal Mokry, Caroline Cheng. Chromatin Conformation Links Distal Target Genes to CKD Loci. Journal of the American Society of Nephrology. 2017; 29 (2):462-476.
Chicago/Turabian StyleMaarten M. Brandt; Claartje A. Meddens; Laura Louzao Martinez; Noortje A.M. Van Den Dungen; Nico R. Lansu; Edward E.S. Nieuwenhuis; Dirk J. Duncker; Marianne C. Verhaar; Jaap A. Joles; Michal Mokry; Caroline Cheng. 2017. "Chromatin Conformation Links Distal Target Genes to CKD Loci." Journal of the American Society of Nephrology 29, no. 2: 462-476.
TextabstractFemale gender, post-menopause, chronic kidney disease (CKD) and (CKD linked) microvascular disease are important risk factors for developing heart failure with preserved ejection fraction (HFpEF). Enhancing our understanding of the interrelation between these risk factors could greatly benefit the identification of new drug targets for future therapy. This review discusses the evidence for the protective role of estradiol (E2) in CKD-associated microvascular disease and related HFpEF. Elevated circulating levels of uremic toxins (UTs) during CKD may act in synergy with hormonal changes during post-menopause and could lead to coronary microvascular endothelial dysfunction in HFpEF. To elucidate the molecular mechanism involved, published transcriptome datasets of indoxyl sulfate (IS), high inorganic phosphate (HP) or E2 treated human derived endothelial cells from the NCBI Gene Expression Omnibus database were analyzed. In total, 36 genes overlapped in both IS- and HP-activated gene sets, 188 genes were increased by UTs (HP and/or IS) and decreased by E2, and 572 genes were decreased by UTs and increased by E2. Based on a comprehensive in silico analysis and literature studies of collected gene sets, we conclude that CKD-accumulated UTs could negatively impact renal and cardiac endothelial homeostasis by triggering extensive inflammatory responses and initiating dysregulation of angiogenesis. E2 may protect (myo)endothelium by inhibiting UTs-induced inflammation and ameliorating UTs-related uremic bleeding and thrombotic diathesis via restored coagulation capacity and hemostasis in injured vessels
J. (Jiayi) Pei; Magdalena Harakalova; Hester Den Ruijter; Gerard Pasterkamp; Dirk J. Duncker; Marianne Verhaar; Folkert Asselbergs; Caroline Cheng. Cardiorenal disease connection during post-menopause: The protective role of estrogen in uremic toxins induced microvascular dysfunction. International Journal of Cardiology 2017, 238, 22 -30.
AMA StyleJ. (Jiayi) Pei, Magdalena Harakalova, Hester Den Ruijter, Gerard Pasterkamp, Dirk J. Duncker, Marianne Verhaar, Folkert Asselbergs, Caroline Cheng. Cardiorenal disease connection during post-menopause: The protective role of estrogen in uremic toxins induced microvascular dysfunction. International Journal of Cardiology. 2017; 238 ():22-30.
Chicago/Turabian StyleJ. (Jiayi) Pei; Magdalena Harakalova; Hester Den Ruijter; Gerard Pasterkamp; Dirk J. Duncker; Marianne Verhaar; Folkert Asselbergs; Caroline Cheng. 2017. "Cardiorenal disease connection during post-menopause: The protective role of estrogen in uremic toxins induced microvascular dysfunction." International Journal of Cardiology 238, no. : 22-30.
Uridine adenosine tetraphosphate (Up4A), a dinucleotide, exerts vascular influence via purinergic receptors (PR). We investigated the effects of Up4A on angiogenesis and the putative PR involved. Tubule formation assay was performed in a three-dimensional system, in which human endothelial cells were cocultured with pericytes with various Up4A concentrations for 5 days. Expression of PR subtypes and angiogenic factors was assessed in human endothelial cells with and without P2Y6R antagonist. No difference in initial tubule formation was detected between Up4A stimulation and control conditions at day 2. In contrast, a significant increase in vascular density in response to Up4A was observed at day 5. Up4A at an optimal concentration of 5 μM promoted total tubule length, number of tubules, and number of junctions, all of which were inhibited by the P2Y6R antagonist MRS2578. Higher concentrations of Up4A (10 μM) had no effects on angiogenesis parameters. Up4A increased mRNA level of P2YRs (P2Y2R, P2Y4R, and P2Y6R) but not P2XR (P2X4R and P2X7R) or P1R (A2AR and A2BR), while Up4A upregulated VEGFA and ANGPT1, but not VEGFR2, ANGPT2, Tie1, and Tie2. In addition, Up4A increased VEGFA protein levels. Transcriptional upregulation of P2YRs by Up4A was inhibited by MRS2578. In conclusion, Up4A is functionally capable of promoting tubule formation in an in vitro coculture system, which is likely mediated by pyrimidine-favored P2YRs but not P2XRs or P1Rs, and involves upregulation of angiogenic factors.
Zhichao Zhou; Ihsan Chrifi; Yanjuan Xu; John Pernow; Dirk Jan Duncker; Daphne Merkus; Caroline Cheng. Uridine adenosine tetraphosphate acts as a proangiogenic factor in vitro through purinergic P2Y receptors. American Journal of Physiology-Heart and Circulatory Physiology 2016, 311, H299 -H309.
AMA StyleZhichao Zhou, Ihsan Chrifi, Yanjuan Xu, John Pernow, Dirk Jan Duncker, Daphne Merkus, Caroline Cheng. Uridine adenosine tetraphosphate acts as a proangiogenic factor in vitro through purinergic P2Y receptors. American Journal of Physiology-Heart and Circulatory Physiology. 2016; 311 (1):H299-H309.
Chicago/Turabian StyleZhichao Zhou; Ihsan Chrifi; Yanjuan Xu; John Pernow; Dirk Jan Duncker; Daphne Merkus; Caroline Cheng. 2016. "Uridine adenosine tetraphosphate acts as a proangiogenic factor in vitro through purinergic P2Y receptors." American Journal of Physiology-Heart and Circulatory Physiology 311, no. 1: H299-H309.
Dilated cardiomyopathy (DCM) is a relatively common heart muscle disease characterized by the dilation and thinning of the left ventricle accompanied with left ventricular systolic dysfunction. Myocardial fibrosis is a major feature in DCM and therefore it is inevitable that corresponding extracellular matrix (ECM) changes are involved in DCM onset and progression. Increasing our understanding of how ECM adaptations are involved in DCM could be important for the development of future interventions. This review article discusses the molecular adaptations in ECM composition and structure that have been reported in both animal and human studies of DCM. Furthermore, we provide a transcriptome-based catalogue of ECM genes that are associated with DCM, generated by using NCBI Gene Expression Omnibus database sets for DCM. Based on this in silico analysis, many novel ECM components involved in DCM are identified and discussed in this review. With the information gathered, we propose putative pathways of ECM adaptations in onset and progression of DCM.
Laura Louzao-Martinez; Aryan Vink; Magdalena Harakalova; Folkert Asselbergs; Marianne C. Verhaar; Caroline Cheng. Characteristic adaptations of the extracellular matrix in dilated cardiomyopathy. International Journal of Cardiology 2016, 220, 634 -646.
AMA StyleLaura Louzao-Martinez, Aryan Vink, Magdalena Harakalova, Folkert Asselbergs, Marianne C. Verhaar, Caroline Cheng. Characteristic adaptations of the extracellular matrix in dilated cardiomyopathy. International Journal of Cardiology. 2016; 220 ():634-646.
Chicago/Turabian StyleLaura Louzao-Martinez; Aryan Vink; Magdalena Harakalova; Folkert Asselbergs; Marianne C. Verhaar; Caroline Cheng. 2016. "Characteristic adaptations of the extracellular matrix in dilated cardiomyopathy." International Journal of Cardiology 220, no. : 634-646.
Background— The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Methods and Results— Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. Conclusions— The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs.
Christian G.M. van Dijk; Nynke R. Oosterhuis; Yan Juan Xu; Maarten Brandt; Walter J. Paulus; Loek van Heerebeek; Dirk J. Duncker; Marianne C. Verhaar; Dulce Fontoura; André P. Lourenço; Adelino F. Leite-Moreira; Inês Falcão-Pires; Jaap A. Joles; Caroline Cheng. Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome. Circulation: Heart Failure 2016, 9, e002760 .
AMA StyleChristian G.M. van Dijk, Nynke R. Oosterhuis, Yan Juan Xu, Maarten Brandt, Walter J. Paulus, Loek van Heerebeek, Dirk J. Duncker, Marianne C. Verhaar, Dulce Fontoura, André P. Lourenço, Adelino F. Leite-Moreira, Inês Falcão-Pires, Jaap A. Joles, Caroline Cheng. Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome. Circulation: Heart Failure. 2016; 9 (4):e002760.
Chicago/Turabian StyleChristian G.M. van Dijk; Nynke R. Oosterhuis; Yan Juan Xu; Maarten Brandt; Walter J. Paulus; Loek van Heerebeek; Dirk J. Duncker; Marianne C. Verhaar; Dulce Fontoura; André P. Lourenço; Adelino F. Leite-Moreira; Inês Falcão-Pires; Jaap A. Joles; Caroline Cheng. 2016. "Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome." Circulation: Heart Failure 9, no. 4: e002760.
The lymphatic system plays a crucial role in interstitial fluid drainage, lipid absorption and immunological defence. Lymphatic dysfunction results in lymphedema, fluid accumulation and swelling of soft tissues, as well as a potentially impaired immune response. Lymphedema significantly reduces quality of life of patients on a physical, mental, social and economic basis. Current therapeutic approaches in treatment of lymphatic disease are limited. Over the last decades, great progress has been made in the development of therapeutic strategies to enhance vascular regeneration. These solutions to treat vascular disease may also be applicable in the treatment of lymphatic diseases. Comparison of the organogenic process and biological organization of the vascular and lymphatic system and studies in the regulatory mechanisms involved in lympangiogenesis and angiogenesis, show many common features. Here, we address the similarities between both transport systems, and focus in depth on the biology of lymphatic development. Based on the current advances in vascular regeneration, we propose different strategies for lymphatic tissue engineering that may be used for treatment of primary and secondary lymphedema. Keywords: lymphangiogenesis, lymphedema, tissue engineering, regenerative medicine, stem cells
Eline Huethorst; Merle M. Krebber; Joost O. Fledderus; Hendrik Gremmels; Yan Juan Xu; Jiayi Pei; Marianne C. Verhaar; Caroline Cheng. Lymphatic Vascular Regeneration: The Next Step in Tissue Engineering. Tissue Engineering Part B: Reviews 2016, 22, 1 -14.
AMA StyleEline Huethorst, Merle M. Krebber, Joost O. Fledderus, Hendrik Gremmels, Yan Juan Xu, Jiayi Pei, Marianne C. Verhaar, Caroline Cheng. Lymphatic Vascular Regeneration: The Next Step in Tissue Engineering. Tissue Engineering Part B: Reviews. 2016; 22 (1):1-14.
Chicago/Turabian StyleEline Huethorst; Merle M. Krebber; Joost O. Fledderus; Hendrik Gremmels; Yan Juan Xu; Jiayi Pei; Marianne C. Verhaar; Caroline Cheng. 2016. "Lymphatic Vascular Regeneration: The Next Step in Tissue Engineering." Tissue Engineering Part B: Reviews 22, no. 1: 1-14.
Pericytes are perivascular cells that can be distinguished from vascular smooth muscle cells by their specific morphology and expression of distinct molecular markers. Found in the microvascular beds distributed throughout the body, they are well known for their regulation of a healthy vasculature. In this review, we examine the mechanism of pericyte support to vasomotion, and the known pathways that regulate pericyte response in angiogenesis and neovascular stabilization. We will also discuss the role of pericytes in vascular basement membrane and endothelial barrier function regulation. In contrast, recent findings have indicated that pericyte dysfunction, characterized by changes in pericyte contractility or pericyte loss of microvascular coverage, plays an important role in onset and progression of vascular-related and fibrogenic diseases. From a therapeutic point of view, pericytes have recently been identified as a putative pool of endogenous mesenchymal stem cells that could be activated in response to tissue injury to contribute to the regenerative process on multiple levels. We will discuss the mechanisms via which pericytes are involved in disease onset and development in a number of pathophysiological conditions, as well as present the evidence that supports a role for multipotent pericytes in tissue regeneration. The emerging field of pericyte research will not only contribute to the identification of new drug targets in pericyte dysfunction associated diseases, but may also boost the use of this cell type in future cell-based regenerative strategies.
Christian G.M. van Dijk; Frederieke E. Nieuweboer; Jia Yi Pei; Yan Juan Xu; Petra Burgisser; Elise van Mulligen; Hamid el Azzouzi; Dirk J. Duncker; Marianne Verhaar; Caroline Cheng. The complex mural cell: Pericyte function in health and disease. International Journal of Cardiology 2015, 190, 75 -89.
AMA StyleChristian G.M. van Dijk, Frederieke E. Nieuweboer, Jia Yi Pei, Yan Juan Xu, Petra Burgisser, Elise van Mulligen, Hamid el Azzouzi, Dirk J. Duncker, Marianne Verhaar, Caroline Cheng. The complex mural cell: Pericyte function in health and disease. International Journal of Cardiology. 2015; 190 ():75-89.
Chicago/Turabian StyleChristian G.M. van Dijk; Frederieke E. Nieuweboer; Jia Yi Pei; Yan Juan Xu; Petra Burgisser; Elise van Mulligen; Hamid el Azzouzi; Dirk J. Duncker; Marianne Verhaar; Caroline Cheng. 2015. "The complex mural cell: Pericyte function in health and disease." International Journal of Cardiology 190, no. : 75-89.