Vascular Nephrology Group Research

The Vascular Nephrology Group was initiated by Anton Jan van Zonneveld and Ton Rabelink in 2004 and research topics are centred around the understanding and clinical translation of molecular mechanisms in vascular injury and repair, secondary to adverse metabolic- or hemodynamic risk factors such as encountered in diabetes, chronic kidney disease or kidney transplantation. The following topics are key areas of research:

Posttranscriptional mechanisms in vascular homeostasis: non-coding RNAs
It is not the number of genes that defines human complexity. While humans have little over twenty thousand genes, a water flea has thirty-one thousand genes. What does drive complexity is how genes are “wired” and can optimally act together like a complicated electrical circuit with amplifying transistors and effective feedback mechanisms. Posttranscriptional regulation provides such a coordinate control of gene expression in response to environmental changes or cellular injury. Facilitated by an intricate interplay between non-coding RNAs such as microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) and RNA-binding proteins gene expression is regulated to drive the output of functionally related cellular pathways. Over the years, supported by grants from a.o. the Dutch Heart Foundation and the Dutch Kidney foundation, we demonstrated pivotal roles for miRNAs in vascular homeostasis, kidney health and disease. For part of this work, published in the thesis “MicroRNAs in Kidney Health and Disease” project leader Roel Bijkerk received the best thesis of the year award in 2014 (Dutch Federation for Nephrology). In addition, our group received the 2015 Novartis Basic Science award for the best pre-clinical publication in transplantation research (Bijkerk, JASN 2014). Current studies involve the role of sex-specific posttranscriptional pathways in heart failure with preserved ejection fraction (HFpEF) in the context of the Dutch Heart Foundation supported Queen of Hearts consortium and the role of circulating miRNAs for the progression of HFpEF in kidney disease in the Dutch Heart Foundation sponsored CVON consortium RECONNECT.

• – Circulating noncoding RNA as posttranscriptional determinant of cardiovascular complications in CKD
• – Post-transcriptional regulation as a key driver of intrinsic kidney regeneration
• – Long noncoding RNAs as a determinant of microvascular stability in chronic kidney disease

• Team members
  Roel Bijkerk, PhD, Au Yu Wah, MSc, Barend Florijn, MD, Jacques Duijs, MSc, Anton Jan van Zonneveld, PhD

Posttranscriptional mechanisms in vascular homeostasis: RNA-binding proteins and splicing
“RNA-binding proteins (RBPs) are the CEO’s of gene regulation” is what project leader Eric van de Veer would explain to you. In human cells, over 700 different RBPs have emerged as pivotal regulators of functional cellular adaptations in the cardiovascular system by guiding a wide-ranging number of post-transcriptional events that dramatically impact RNA fate, including alternative splicing, stability, localization and translation. In recent years Eric and his PhD students published several seminal publications on the function of the RNA-binding protein Quaking in major cell types of the cardiovascular system. Based on his collective work, with PhD student Ruben de Bruin (Doctorate cum laude in 2018), he recently published an invited review on the role of RBPs in cardiovascular disease in the European Heart Journal. Moreover, in 2016 Eric was awarded the prestigious Irvine H. Page Young Investigator Award by the ATVB Society for his study detailing the role of Quaking in regulating monocyte and macrophage function in the setting of atherosclerosis. Dr. van der Veers current research efforts focus on the role of Quaking in the formation of circular RNAs (2017 Rembrandt Award, collaboration Dr. E. Creemers AMC) and translating our knowledge on the modulation of splicing to the clinical arena.

• – Limiting pro-atherogenic macrophage formation: Taming Quaking and inflammation
• – Maintaining healthy perivascular stromal cells: Zooming in on vascular smooth muscle cell and pericyte biology
• – Post-transcriptional investigation of platelet aggregation
• – Protecting the endothelium: Post-transcriptional control of barrier function by Quaking

• Team members
  Jurriën Prins, MSc, Jacques Duijs, MSc, Janneke Kouwenberg, BSc, Eva Argiro BSc, Anton Jan van Zonneveld, PhD

Coagulation, platelets and inflammation in vascular injury and repair
Chronic systemic inflammation and activation of the coagulation system are common mechanistic denominators in microvascular destabilization in kidney transplant patients or patients with atrial fibrillation (AF) or HFpEF. Project leader Hetty de Boer has a longstanding interest in hemostasis and the biology of platelets. Early papers demonstrated the key role of platelet activation in endothelial progenitor biology and vascular homeostasis. More recently, a seminal paper in the European Heart Journal of revealed the etiology of circulating angiogenic microRNA-126. Also in the context of the Dutch Heart Foundation sponsored CVON consortium RACE V we study the hypothesis that coagulation activation is a causal factor in microvascular rarefaction (loss) in the atria of AF patients thereby leading to the progression of the disease.
Currently, this research line focuses on the phenotypes of circulating monocytes in chronic kidney disease.

• – Platelets are instrumental in the mobilization and differentiation of hematopoietic stem cells at the site of a vascular injury
• – Platelets plug a breached vessel wall, but may support the activation of coagulation under AF-conditions
• – The role of Quaking (isoforms) in platelet aggregation
• – Monocyte conversion in patient cohorts

• Team members
  Hetty de Boer, PhD, Annemarie van Oeveren-Rietdijk, MSc, Sophie Dolleman, MSc, Edwin Bredewold, MD, Angela Koudijs, BAS, Anton Jan van Zonneveld, PhD

Neuronal guidance cues in inflammation and vascular biology
Chronic systemic inflammation is a driver of both the macrovascular disease atherosclerosis as well as diseases associated with the loss of the microvasculature such as HFpEF. The ligands and receptors of the Neuronal Guidance Cues (NGCs) are emerging as significant regulators of inflammation. Project leader Janine van Gils, supported by a personal, senior Postdoc grant from the Dutch Heart Foundation, is investigating the role of NGCs in endothelial biology and inflammation and aims to take the next step towards translation and assess the clinical relevance in patients with coronary artery disease. In collaboration with Professor Cees Hovingh (AMC), Janine received the prestigious Rembrandt Institute on Cardiovascular Science Award to investigate whether deficiencies in NGCs are the culprit in families with premature atherosclerosis.

• – Neuroimmune guidance cues to combat atherosclerosis
• – The role of human genetic variations in neuronal guidance cues in premature atherosclerosis
• – Neuroimmune guidance cues, MicroRNAs & Inflammatory responses: Sex differences in CardioVascular Diseases

• Team members
  Janine van Gils, PhD, Huaya Zhang, MSc, Dianne Vreeken, MSc, Caroline Bruikman, MSc (AMC), Anton Jan van Zonneveld, PhD

Innovative 3D microvessel-on-a chip models
In a collaboration between our group, the group of professor Thomas Hankemeier (Analytical BioSciences at the LACDR) and organ-on-a-chip company MIMETAS (Leiden) we recently developed a microfluidics-based, 3D ‘microvessel-on-a-chip’ platform that allows the modeling of patient- or disease-specific human pericyte-stabilized microvessels and allows quantitative and parallel testing of microvascular leakage, angiogenesis and inflammation. We aim to apply our platform to serve as a novel diagnostic and prognostic tool as well as a unique technology to develop therapeutic strategies to combat the loss of microvascular integrity in a broad spectrum of systemic diseases including cardiovascular disease, obesity and its complications. This work is in part supported by a ZonMw grant in the Meer Kennis Minder Dieren (MKMD) program aimed at validating the physiological relevance of our model. In addition The Dutch Heart Foundation consortium CVON RECONNECT.

• Team member
  Abidemi Junaid, MSc (LACDR/LUMC), Vincent van Duinen, MSc (LUMC/LACDR), Loïs van der Pluijm, MSc, Wendy Stam, BSc, Janine van Gils, PhD, Anton Jan van Zonneveld, PhD

Former group members:
Eric van der Veer, PhD
Ruben de Bruin, MD, PhD
Marina Aleksinskaya, post-doc
Coen van Solingen, PhD (post-doc)
Lucie Baldeon, PhD (Erasmus)
Matthieu Monge, MD
Marco Roeten, technician
Joost Vos, post-doc
Cindy Loomans, PhD
Caroline Verseyden, technician
Lonneke Bevers, PhD