Blood Vessel Development




Koo, Yeon Seung

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Cardiovascular system is the first developing functional organ in vertebrates, and one of the fundamental organ systems through adulthoods. Cardiovascular function depends on patent blood vessel formation by endothelial cells. In this dissertation, a careful analysis of different aspects of blood vessel development was conducted in order to expand our understandings of the biology of blood vessel. In brief, Chapter 2 provides an in depth description of vessel anatomy during formation of the first arteries and veins in developing murine embryos, and a stepwise acquisition of arteriovenous fate in these vessels. The dorsal aortae, the first intraembryonic vessels initiate arterial specification before complete circulation occurs, and gradually express a subset of arterial genes. The first veins then establish their fate later than the first arteries. It was also shown that the arteriovenous specification does not require hemodynamic flow, but the flow affects maintenance of select arterial genes. Chapter 3 focuses on the function of Rasip1 in vasculogenesis, angiogenesis and vessel maintenance in developing embryo and in adults. An observation of transient Rasip1 localization at apical membranes in endothelial cells during in vitro tube formation provided an insight where Rasip1 possibly functions. Mice lacking Rasip1 showed that Rasip1 is critical for lumen formation likely via recruiting Myosin to endothelial apical membranes to alter cell cytoskeleton during vasculogenesis. Rasip1 was also shown to be required for proper vessel remodeling and lumen formation during angiogenesis. I found, however, it is dispensable for adult established blood vessel lumen maintenance, making it a promising therapeutic target for anti-angiogenesis. Finally, in Chapter 4, I show my preliminary findings regarding the role of Arhgap29, a Rasip1 binding partner, during embryonic development. Genetic ablation of Arhgap29 in mice led to allantois-chorion fusion and cardiovascular defects during embryonic development. Arhgap29 expression patterns were correlated with the sites of defects, as Arhgap29 transcripts were seen in allantois and cardiovascular tissues. From these results, its potential role in regulation of cell adhesion, likely via RhoA, was suggested. Overall, this thesis describes basic aspects of vascular development and uncharacterized molecules in different aspects of cardiovascular function.

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