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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.
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.
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.