Making a functional vascular system: How Semaphorin-PlexinD1 signaling regulates development of the zebrafish segmental artery.

The vascular system is the largest organ in the human body and its proper development is crucial for homeostasis and survival. Abnormalities of vascular development and function have great impact on human health and contribute to cancer, heart diseases and diabetes, which are leading causes of death in developed countries. The vascular system develops in two stages. The first stage is de novo formation of major blood vessels. During this stage endothelial cells are specified and migrate to specific locations and coalesce into cords and plexuses from which major vessels of the body, such as aorta and vena cava, are formed. The second stage of vascular development is called angiogenesis. During this stage new vessels are made from preexisting vessels via sprouting angiogenesis, bridging or intussusception. Yet, what are the mechanisms that spatially allocate angiogenic capacity to ensure the stereotypical formation of vascular beads remains to be understood. My work has mainly focused on understanding of the process of sprouting angiogenesis in zebrafish segmental arteries. We were able to show that Semaphorin-PlexinD1 (Sema-PlxnD1) signaling plays a novel role in orchestrating the development of zebrafish segmental arteries by regulating the abundance of a decoy Vascular Endothelial Growth Factor (VEGF) receptor sflt1 . By doing so, Sema-PlxnD1 signaling is able to spatially regulate the levels of VEGF signaling and thus assures that zebrafish segmental arteries launch from reproducible positions and in the proper abundance. In addition I analyzed the formation and fusion of the paired Dorsal Longitudal Anastomotic Vessels (DLAVs) in the zebrafish embryo. For the first time we observed the fusion and rearrangement processes between two DLAVs, which results in an emergence of new structure, which we call Dorsal Medial Plexus (DMP). Further molecular analysis of DMP showed that its formation is regulated by blood flow and VEGF signaling. Together, our findings provide novel mechanisms that add to our understanding of how segmental arteries are formed and how preexisting vessels remodel in order to give rise to a functional vascular system.