The goal of our lab is to understand the processes that are important for the proper formation of the cardiovascular system, which is the first organ system to form during development. It consists of an elaborately branched blood vessel tree, providing nutrients and oxygen to all parts of the body. Until 10 years ago, it was thought that the 2 main blood vessel types, arteries and veins differ solely in terms of their physiological properties: arteries carry oxygenated blood away from the heart and experience higher blood pressure, while veins have lower blood pressure and transport blood back to the heart. Since then it has become clear that arteries and veins are molecularly distinct even before the onset of blood flow and many arterial and venous specific marker genes have been identified. In addition, we begin to understand which signalling pathways help to pattern the cardiovascular system. Among these, the Notch and VEGF (Vascular Endothelial Growth Factor) signalling pathways have been shown to function in arterial differentiation and during the sprouting of new blood vessels from pre-existing ones, a process called angiogenesis.
Despite these recent advances, many open questions remain as of how endothelial cells coordinate their behaviours during the formation of the cardiovascular system. In order to better understand these processes, we utilize zebrafish as a model organism. The embryos of these fish offer unique advantages for the study of forming blood vessels. Available transgenic lines, marking endothelial cells with fluorescent proteins allow the in vivo observation of the developing vascular system. In addition, forward and reverse genetic tools permit a detailed analysis of the genes important for endothelial development. Moving forward, an increased understanding of the mechanisms that pattern the cardiovascular system will help us in developing strategies for curing diseases with a vascular component, such as diabetes, stroke and cancer. Some of the ongoing projects are summarized below.
Notch Signalling in Endothelia Cells
In addition to its role during arterial differentiation Notch signalling plays an important role during angiogenesis. Recent work has demonstrated that endothelial cells within a given blood vessel sprout exhibit distinct behaviours, such as migration and proliferation, which are controlled by differential Notch signalling activity. Despite these differences, Notch ligands and receptors are expressed in all arterial endothelial cells. One focus of our laboratory is to identify the mechanisms responsible for temporally and spatially distinct Notch activation within endothelial cells.
Endothelia Cell Migration
During the formation of the vascular tree, endothelial cells need to respond to appropriate guidance cues in order to arrive at their target tissue and connect with the existing vasculature. However, not all endothelial cells should respond to the same guidance cues, as this would lead to misconnections between blood vessels and shunting. We would like to find out how endothelial cells migrate through tissues and the signalling pathways responsible for the correct targeting of endothelial cells. Furthermore, we would like to understand how endothelial cells distinguish between different guidance cues.
Endothelia Cell Dfferentiation in Different Vascular Beds
In addition to the identification of arterial and venous specific genes, recent work has shown that arteries within different vascular beds, such as the brain or the gut, are molecularly distinct. We are interested in the mechanisms responsible for these differences and how they impinge on vascular function. In order to address this question, we are analysing the promoters for genes expressed in given vascular beds.
Migration of endothelial cells in intersomitic blood vessel sprouts.
Selected Publications:
Siekmann, A.F., Standley, C., Fogarty, K.E., Wolfe, S.A., Lawson, N.D. (2009)
Chemokine signaling guides regional patterning of the first embryonic artery.
Genes and Development (in press).
Covassin L.D., Siekmann, A.F., Kacergis, M.C., Laver, E., Moore, J.C., Villefranc, J.A., Weinstein, B.M., Lawson, N.D. (2009)
A genetic screen for vascular mutants in zebrafish reveals dynamic roles for Vegf/Plcg1 signaling during artery development.
Developmental Biology, 15;329(2):212-26.
Siekmann, A.F. and Lawson, N.D. (2007)
Notch signaling limits angiogenic cell behavior in developing zebrafish arteries.
Nature, 15;445(7129):781-4.
Siekmann, A.F. and Lawson, N.D. (2007).
Notch Signaling and the Regulation of Angiogenesis. Cell Adhesion & Migration, 1:2, 104-106.
Siekmann, A.F., Covassin, L., Lawson, N.D. (2008).
Modulation of VEGF signaling output by the Notch pathway.
Bioessays, 30(4):303-13.
