The emergence of complex diseases resulting from abnormal cell-cell signaling and the spread of infectious diseases caused by pathogens are significant threats to humanity. Unraveling the dynamic... Show moreThe emergence of complex diseases resulting from abnormal cell-cell signaling and the spread of infectious diseases caused by pathogens are significant threats to humanity. Unraveling the dynamic mechanisms underlying cell-cell signaling and infectious disease spreading is crucial for effective disease prevention and treatment. As science and technology advance, the availability and diversity of observational and experimental data related to these biological processes continue to grow. In this thesis, we integrate multisource data with dynamic modeling to investigate the biological mechanisms of Notch signaling in biological development and to develop prevention and control strategies for infectious diseases. Show less
Vascular remodeling is an active process of structural changes in the vasculature due to changes in the blood flow. It comprises diseases and processes such peripheral artery disease (PAD),... Show moreVascular remodeling is an active process of structural changes in the vasculature due to changes in the blood flow. It comprises diseases and processes such peripheral artery disease (PAD), coronary artery disease (CAD), neovascularization and vein graft disease (VGD), that are covered by cardiovascular diseases (CVD). The main underlying pathology of CVD is atherosclerosis, which can cause ischemia distal to atherosclerotic occlusions. Neovascularization (angiogenesis and arteriogenesis) naturally occurs in the body to form new blood vessels and restore blood flow to ischemic tissue. In case of severe atherosclerotic lesions, when the neovascularization capability of the body is not sufficient and revascularization interventions are no longer possible, bypass surgery is indicated with preferaby a vein graft. However, due to VGD, patency rates of vein grafts after 10 years are low. The aim of this thesis was to elucidate the role of the innate and adaptive immune system on vascular remodeling. We investigated the role of Toll-like receptors, Interferon regulatory factors and T cells on neovascularisation and VGD. In conclusion, new knowledge was obtained on several contributing factors in vascular remodeling. Described molecules of the innate and adaptive immune system might be used as targets to prevent VGD and stimulate neovascularization. Show less
One of the major limitations in culturing complex tissues or organs is the lack of vascularization in the cultured tissue. Development of a functional capillary bed could overcome this problem.... Show moreOne of the major limitations in culturing complex tissues or organs is the lack of vascularization in the cultured tissue. Development of a functional capillary bed could overcome this problem. The zebrafish is a promising model for in vitro vasculogenesis and angiogenesis studies, as a replacement for currently used mammalian models. However, the culture of endothelial cells from this species is not well characterized. Here, we test different culture strategies, medium supplementations and culture substrates for their effect on the generation of putative endothelial (fli:GFP+ and kdrl:GFP+) cells and vascular morphogenesis in zebrafish blastocyst cell derived embryoid body culture. we have also developed a perfused culture model, using microfluidic technology, to culture zebrafish vascular networks. This study is a step forward to the development of zebrafish vascular networks in vitro. Show less
This thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in... Show moreThis thesis details our studies assessing the role of the endothelial-enriched miRNA-126 in the regulation of vascular homeostasis. In Chapter 2 the current insight in the role of miRNA-126 in vascular homeostasis is reviewed. Chapter 3 focuses on the role of miRNA-126 in ischemia induced angiogenesis, followed by Chapter 4 which describes the potential role of miRNA-126 the mobilization of vasculogenic progenitor cells upon ischemia. Both chapters utilize antagomir-technology to specifically silence miRNA-126 in vivo. This approach to silence miRNA-126 was also used in Chapter 5 to elucidate the regulatory role of miRNA-126 in vascular cell adhesion molecule-1 expression in the kidney vasculature. Chapter 6 details our findings that circulating miRNA-126 in the periphery is not exclusively derived from endothelial cells but can also originate from platelets. Consequently, the use of aspirin has to be taken into account when relating circulating miRNA-126 levels to the progression of cardiovascular disease. Chapter 7 demonstrates that the angiogenic potential of miRNA-126 as described in Chapter 3 might reach beyond the presence of this pro-angiogenic miRNA in endothelium, but that neovascularization can also be supported by miRNA-126 expressed in circulating cells. Finally, Chapter 8 provides a summary of research presented in this thesis, presents the major conclusions that could be drawn and further discusses the role of miRNA-126 in vascular homeostasis. Show less
