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Angiogenesis is essential for physiological processes including embryonic development, tissue regeneration, and reproduction. Under various pathological conditions the same angiogenic process contribute to the onset, development, and progression of many human diseases including cancer, diabetic complications, ocular disease, chronic inflammation and cardiovascular disease. Vascular endothelial growth factor (VEGF) is a key angiogenic factor for physiological and pathological angiogenesis. In addition to its strong angiogenic activity, VEGF also potently induces vascular permeability, often causing tissue edema in various pathological tissues. VEGF transduces its vascular signal through two tyrosine kinase receptors-VEGFR1 and VEGFR2, the latter being a functional receptor that mediates both angiogenic and vascular permeability effects. To study physiological and pathological functions of VEGF, we developed novel zebrafish disease models that permit us to study hypoxia-induced retinopathy and cancer metastasis processes. We have also administered anti-VEGF and anti-VEGFR specific antibodies to healthy mice to study the homeostatic role of VEGF in the maintenance of vascular integrity and its functions in various tissues and organs. Finally, using a zebrafish model, we evaluated if VEGF expression is regulated by circadian clock genes. In paper I, we developed protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1:EGFP zebrafish were placed in hypoxic water for 3-10 days with retinal neovascularization being analyzed using confocal microscopy. This model provides a unique opportunity to kinetically study the development of retinopathy in adult animals using non-invasive protocols and to assess the therapeutic efficacy of orally administered anti-angiogenic drugs. In paper II, we developed a zebrafish metastasis model to dissect the complex events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells were implanted into the perivitelline cavity of 48-hour-old zebrafish embryos, which were subsequently placed in hypoxic water for 3 days. Tumor cell invasion, metastasis and pathological angiogenesis were analyzed using fluorescent microscopy in the living fish. The average experimental time for this model is 7 days. Our protocol offers an opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis. In paper III, we show that systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody cause global vascular regression in mice. Among all examined tissues, the vasculature in endocrine glands, intestinal villi, and the uterus are most affected in response to VEGF or VEGFR-2 blockades. Pro-longed anti-VEGF treatment resulted in a significant decrease in the circulating levels of the predominant thyroid hormone, free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid function. These findings provide structural and functional bases of anti-VEGF-specific druginduced side effects in relation to vascular changes in healthy tissues. In paper IV, we show that disruption of the circadian clock by constant exposure to light coupled with genetic manipulation of key genes in the zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. These results offer mechanistic insights into the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis. Overall, the results in this thesis provide further insight to angiogenic mechanistic properties in tissues and suggest possible novel therapeutic targets for the treatment of various angiogenesis-dependent diseases.
The endothelium, a monolayer of endothelial cells, constitutes the inner cellular lining of the blood vessels (arteries, veins and capillaries) and the lymphatic system, and therefore is in direct contact with the blood/lymph and the circulating cells. The endothelium is a major player in the control of blood fluidity, platelet aggregation and vascular tone, a major actor in the regulation of immunology, inflammation and angiogenesis, and an important metabolizing and an endocrine organ. Endothelial cells controls vascular tone, and thereby blood flow, by synthesizing and releasing relaxing and contracting factors such as nitric oxide, metabolites of arachidonic acid via the cyclooxygenases, lipoxygenases and cytochrome P450 pathways, various peptides (endothelin, urotensin, CNP, adrenomedullin, etc.), adenosine, purines, reactive oxygen species and so on. Additionally, endothelial ectoenzymes are required steps in the generation of vasoactive hormones such as angiotensin II. An endothelial dysfunction linked to an imbalance in the synthesis and/or the release of these various endothelial factors may explain the initiation of cardiovascular pathologies (from hypertension to atherosclerosis) or their development and perpetuation. Table of Contents: Introduction / Multiple Functions of the Endothelial Cells / Calcium Signaling in Vascular Cells and Cell-to-Cell Communications / Endothelium-Dependent Regulation of Vascular Tone / Conclusion / References
New updated edition first published with Cambridge University Press. This new edition includes 29 chapters on topics as diverse as pathophysiology of atherosclerosis, vascular haemodynamics, haemostasis, thrombophilia and post-amputation pain syndromes.
The book presents the overview of the current knowledge in some fields of vascular biology, addressing cellular and molecular aspects of blood-vessel formation and their role in health and disease. The major factors involved in the formation of blood vessels are presented by scientists actively involved in this area of research. Special emphasis is put on the presentation of various molecular mechanisms not addressed in similar works to date. The book is divided into three parts. The first part describes the cells and mediators in angiogenesis. The significance of various populations of potential endothelial progenitors is particularly highlighted. The chapters of the second part focus on molecular mechanisms, with special emphasis on the role of hypoxia, gasotransmitters and reactive oxygen species as well as microRNAs in regulation of angiogenic processes. In the third part, the pathological aspects of disturbed – aggravated or impaired – vascularization are discussed and new modalities for potential therapies are presented. The book is intended for scientists and PhD students in the fields of vascular biology and cancer research. It may be of interest for medical professionals in the fields of cardiovascular disease, diabetes, oncology and rheumatoid arthritis.
The formation of blood vessels is an essential aspect of embryogenesis in vertebrates. It is a central feature of numerous post-embryonic processes, including tissue and organ growth and regeneration. It is also part of the pathology of tumour formation and certain inflammatory conditions. In recent years, comprehension of the molecular genetics of blood vessel formation has progressed enormously and studies in vertebrate model systems, especially the mouse and the zebrafish, have identified a common set of molecules and processes that are conserved throughout vertebrate embryogenesis while, in addition, highlighting aspects that may differ between different animal groups. The discovery in the past decade of the crucial role of new blood vessel formation for the development of cancers has generated great interest in angiogenesis (the formation of new blood vessels from pre-existing ones), with its major implications for potential cancer-control strategies. In addition, there are numerous situations where therapeutic treatments either require or would be assisted by vasculogenesis (the de novo formation of blood vessels). In particular, post-stroke therapies could include treatments that stimulate neovascularization of the affected tissues. The development of such treatments, however, requires thoroughly understanding the developmental properties of endothelial cells and the basic biology of blood vessel formation. While there are many books on angiogenesis, this unique book focuses on exactly this basic biology and explores blood vessel formation in connection with tissue development in a range of animal models. It includes detailed discussions of relevant cell biology, genetics and embryogenesis of blood vessel formation and presents insights into the cross-talk between developing blood vessels and other tissues. With contributions from vascular biologists, cell biologists and developmental biologists, a comprehensive and highly interdisciplinary volume is the outcome.
This book surveys healthy and diseased vascular systems in a multitude of model organisms and systems. It explores a plethora of functions, characteristics, and pathologies of the vascular system such as angiogenesis, fibroblast growth factor signaling, lymphangiogenesis, junctional signaling, the extracellular matrix, vascular permeability, leukocyte extravasation, axon guidance factors, the angiopoietin system, and chronic obstructive lung disease. Following a preface from leading researcher Dr. Holger Gerhardt, the text is divided into three sections- the first examining the development of the vascular system in a variety of contexts, the second delving into its homeostatic characteristics, and the third discussing its pathophysiologies. The sixteen chapters, which represent international clinical and research perspectives, highlight the importance of molecular and signaling pathways for translational basic science and clinical medicine. Additionally, the text explores new and exciting fields in vascular biology research. Comprehensive in both content and approach, Vascular Signaling in Health and Disease is ideal for graduate students, researchers, and clinicians interested in vascular biology, pneumology, and molecular biology.
The Pulmonary Endothelium is a uniquely comprehensive compendium of our current knowledge of the pulmonary endothelium and is the first book dedicated specifically to the subject, offering insights into current and future approaches to management. The text provides the clinician with the most up-to-date information on one of the core physiological processes in airway disease and is an ideal point of reference for both postgraduates and professionals – specialist physicians in pulmonology and allergy and workers in biomedical and pharmaceutical research.
The purpose of this book is to highlight novel advances in the field and to incentivize scientists from a variety of fields to pursue angiogenesis as a research avenue. Blood vessel formation and maturation to capillaries, arteries, or veins is a fascinating area which can appeal to multiple scientists, students, and professors alike. Angiogenesis is relevant to medicine, engineering, pharmacology, and pathology and to the many patients suffering from blood vessel diseases and cancer, among others. We are hoping that this book will become a source of inspiration and novel ideas for all.
This book covers vascular endothelial growth factor A (VEGF or VEGFA), a secreted signaling protein. It highlights the central importance of this growth factor for vertebrate development.