Vessel formation in development and disease


 
Figure 1: TrkB-LacZ transgenic mouse. The TrkB neurotrophin receptor is activated (blue staining) during embryonic development in the heart (H), coelomic epithelium (CE), and the urogenital system.

The cardiovascular system is the first functional organ system required for embryonic survival. Many major diseases and pathophysiological processes are associated with vessel formation, e.g. coronary artery disease, peripheral arterial diseases, liver fibrosis, wound healing, graft rejection, or cancer. Chronic ischemic heart disease, myocardial infarction, and cancer are the most common causes for morbidity and mortality. In ischemic heart disease, angiogenesis is required for collateral vessel formation and therefore a “friend”, in cancer it becomes a “foe” by inducing the transition of a tumour from a small cluster of malignant cells to a macroscopic tumour capable of spreading to other organs via the vasculature. As an important factor in vessel formation, the reduced oxygen supply (hypoxia), which results in stabilization of hypoxia-inducible factor 1 (HIF-1) and subsequent activation of its downstream target genes has been postulated. We described the Wilms’ tumour suppressor 1 transcription factor (WT1) as a target gene of HIF-1. A survived myocardial infarction (MI) results in a long run in collateral formation and the development of cardiac hypertrophy. This collateral formation resembles the formation of coronary vessels during embryonic development. We identified WT1 as an important molecule for coronary vessel formation during embryonic development and furthermore for neovascularization after myocardial infarction. More recently we showed that WT1 is a major regulator of tumour angiogenesis and cancer progression. As molecules regulated by WT1 in angiogenesis, we identified so far the TrkB neurotrophin receptor, the intermediate filament protein nestin, the ETS1 transcription factor, the podocyte protein nephrin, the telomeric protein TRF2, the proto-oncogene c-Kit, and the Platelet endothelial cell adhesion molecule (PECAM-1).

 

 
Figure 2: Pecam-1 staining and 3D reconstruction of the developing coronary vessels in a wild-type (a) and nephrin knockout (b) embryo.

 

The aims of our current projects are to translate our findings into potential novel therapeutic approaches and to further understand the mechanisms of vessel formation. As besides endothelial cells, different cell types, e.g. hematopoietic progenitor and myeloid derived cells, pericytes and smooth muscle cells are involved in vessel formation and maturation, we use mainly analyses in mice in vivo (reporter and lineage tracing strains, inducible knockout / overexpression / knockin mice). The in vivo data are supported by cell culture systems and molecular approaches.

 


 
Figure 3: Overlapping expression of WT1 and Nestin in tumour vessels of an ovary carcinoma.
 
 
Figure 4: Inducible knockout of WT1 in endothelial, hematopoietic, and myeloid derived cells induces vessel and tumour regression.

 

Last publications

Small RNA-directed epigenetic programming of embryonic stem cell cardiac differentiation. - 2017 - Scientific reports - 7 P41799 - Ghanbarian H, Wagner N, Michiels JF, Cuzin F, Wagner KD, and Rassoulzadegan,M

CDK9 regulates apoptosis of myoblast cells by modulation of microRNA-1 expression. - 2017 - Journal of cellular biochemistry - Tarhriz V, Wagner KD, Masoumi Z, Molavi O, Hejazi MS, and Ghanbarian,H

The differential spatiotemporal expression pattern of shelterin genes throughout lifespan. - 2017 - Aging - 9 P1219-1232 - Wagner KD, Ying Y, Leong W, Jiang J, Hu X, Chen Y, Michiels JF, Lu Y, Gilson E, Wagner N, and Ye,J

Coronary Artery Formation Is Driven by Localized Expression of R-spondin3. - 2017 - Cell reports - 20 P1745-1754 - Da Silva F, Rocha AS, Motamedi FJ, Massa F, Basboga C, Morrison H, Wagner KD, and Schedl,A

RNA activation of the VEGF promoter by dsRNA and hypoxia: Role of non-coding VEGF promoter transcripts. - 2016 - Molecular and cellular biology - Lopez P, Wagner KD, Hofman P, and Van Obberghen,E

Inducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy. - 2016 - PPAR research - 2016 P7631085 - Wagner KD, Vukolic A, Baudouy D, Michiels JF, and Wagner,N

Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections. - 2016 - Proceedings of the National Academy of Sciences of the United States of America - 113 P656-61 - Cano E, Carmona R, Ruiz-Villalba A, Rojas A, Chau YY, Wagner KD, Wagner N, Hastie ND, Muñoz-Chápuli R, and Pérez-Pomares,JM

Dnmt2/Trdmt1 as Mediator of RNA Polymerase II Transcriptional Activity in Cardiac Growth. - 2016 - PloS one - 11 Pe0156953 - Ghanbarian H, Wagner N, Polo B, Baudouy D, Kiani J, Michiels JF, Cuzin F, Rassoulzadegan M, and Wagner,KD

The Telomeric Protein TRF2 Regulates Angiogenesis by Binding and Activating the PDGFRβ Promoter. - 2014 - Cell reports - 9 P1047-60 - El Maì¯ M, Wagner KD, Michiels JF, Ambrosetti D, Borderie A, Destree S, Renault V, Djerbi N, Giraud-Panis MJ, Gilson E, and Wagner,N

The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression. - 2014 - Nature communications - 5 P5852 - Wagner KD, Cherfils-Vicini J, Hosen N, Hohenstein P, Gilson E, Hastie ND, Michiels JF, and Wagner,N

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Wagner Kay
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2015 Grand Prix Cancérologie Fondation Simone et Cino del Duca, Academie des sciences

2007 INSERM AVENIR

2007 Du Bois-Reymond-Prize, German Physiological Society

2003 EMBO Long-term Fellow

1998 Robert-Koch-Prize, Charité, Germany

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