Vascular diseases pose a significant burden on society, mainly due to the lack of effective treatment methods. A major reason for this is the shortcomings of current preclinical model systems. In... Show moreVascular diseases pose a significant burden on society, mainly due to the lack of effective treatment methods. A major reason for this is the shortcomings of current preclinical model systems. In this study, we have taken steps toward developing a more complex and relevant model system for (brain) blood vessels to address this issue. We used human induced pluripotent stem cells (hiPSCs) in the lab as a cellular source to generate the different types of cells needed for stable blood vessels. These cells were then combined in 3D microscopic culture environments (so-called vessel-on-chip systems) to closely mimic physiological conditions. Using this model, we were able to demonstrate specific abnormalities in a hereditary vascular disease, which was not possible with more 'traditional' culture methods. Additionally, we included brain cells to better investigate brain-specific disorders in the future. This work lays the essential foundation for a better understanding and treatment of complex vascular diseases, while potentially reducing the number of animal models needed. Show less
Galaris, G.; Thalgott, J.H.; Lebrin, F.P.G.; Birbrair, A. 2019
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many... Show moreHereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-beta and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT. Show less
Cai, J.; Pardali, E.; Sanchez-Duffhues, G.; Dijke, P. ten 2012
