http://repub.eur.nl/res/aut/19332/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/26735/ 2011-10-19T00:00:00Z Aelius Galenus (AD 129 – 199) was one of the first persons to explore the blood vasculature. During his work as physician and surgeon, he recognized distinct differences in blood vessels. During surgery, he observed that vessels were filled with either dark or bright blood. He believed that the human blood vascular system contained two one-way blood distribution routes. The dark (venous) blood was generated directly from food uptake in the liver, whereas the bright (arterial) blood was generated in the heart. From the heart and liver, blood was then equally distributed and ‘consumed’ by all other organs in the body. To complete the vascular system, blood was then regenerated in either the heart or liver (reviewed in (Carmeliet, 2005). This ‘two-one way circulation’ theory was believed for centuries and it was only until the 16th century that the British biologist and medical doctor William Harvey could show that Galenus was wrong. Harvey characterized and quantified the blood volume which passes the heart and concluded that this was much larger than the amount of blood that could be generated by the body itself (On the Motion of the Heart and Blood in Animals, 1628, William Harvey). Harvey postulated that there had to be a circulatory loop in the body which consisted of the heart and a connected vessel system. With a simple experiment, by tightening a ligature on to the upper arm of an individual, he indeed identified a circulatory loop which was connected to the heart and identified the presence of arteries and veins but also functional differences between arteries and veins (On The Motion Of The Heart And Blood In Animals, 1628, William Harvey, (Carmeliet, 2005). http://repub.eur.nl/res/pub/31154/ 2011-08-05T00:00:00Z Rationale: Neovascularization is required for embryonic development and plays a central role in diseases in adults. In atherosclerosis, the role of neovascularization remains to be elucidated. In a genome-wide microarray-screen of Flk1+ angioblasts during murine embryogenesis, the v-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) transcription factor was identified as a potential angiogenic factor. Objectives: We assessed the role of Ets2 in endothelial cells during atherosclerotic lesion progression toward plaque instability. Methods and Results: In 91 patients treated for carotid artery disease, Ets2 levels showed modest correlations with capillary growth, thrombogenicity, and rising levels of tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1, and interleukin-6 in the atherosclerotic lesions. Experiments in ApoE mice, using a vulnerable plaque model, showed that Ets2 expression was increased under atherogenic conditions and was augmented specifically in the vulnerable versus stable lesions. In endothelial cell cultures, Ets2 expression and activation was responsive to the atherogenic cytokine TNFα. In the murine vulnerable plaque model, overexpression of Ets2 promoted lesion growth with neovessel formation, hemorrhaging, and plaque destabilization. In contrast, Ets2 silencing, using a lentiviral shRNA construct, promoted lesion stabilization. In vitro studies showed that Ets2 was crucial for TNFα-induced expression of monocyte chemoattractant protein 1, interleukin-6, and vascular cell adhesion molecule 1 in endothelial cells. In addition, Ets2 promoted tube formation and amplified TNFα-induced loss of vascular endothelial integrity. Evaluation in a murine retina model further validated the role of Ets2 in regulating vessel inflammation and endothelial leakage. Conclusions: We provide the first evidence for the plaque-destabilizing role of Ets2 in atherosclerosis development by induction of an intraplaque proinflammatory phenotype in endothelial cells. http://repub.eur.nl/res/pub/28141/ 2010-08-15T00:00:00Z The endothelial cells of the vertebrate lymphatic system assemble into complex networks, but local cues that guide the migration of this distinct set of cells are currently unknown. As a model for lymphatic patterning, we have studied the simple vascular network of the zebrafish trunk consisting of three types of lymphatic vessels that develop in close connection with the blood vasculature. We have generated transgenic lines that allow us to distinguish between arterial, venous and lymphatic endothelial cells (LECs) within a single zebrafish embryo. We found that LECs migrate exclusively along arteries in a manner that suggests that arterial endothelial cells serve as the LEC migratory substrate. In the absence of intersegmental arteries, LEC migration in the trunk is blocked. Our data therefore demonstrate a crucial role for arteries in LEC guidance. http://repub.eur.nl/res/pub/16241/ 2009-04-01T00:00:00Z Lymphatic vessels have important roles in fluid homeostasis, fat absorption, inflammation and cancer metastasis and develop in a dynamic process (called lymphangiogenesis) involving budding, migration and proliferation of lymphangioblasts. Using a genetic screen in zebrafish we identify ccbe1 (collagen and calcium-binding EGF domain-1) as indispensible for embryonic lymphangiogenesis. Ccbe1 acts at the same stage of development as Vegfc and is required for lymphangioblast budding and angiogenic sprouting from venous endothelium.