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Research Overview
Our work aims at understanding the mechanisms that lead to the correct formation of the intricate networks of blood vessels within our bodies. These networks are vital for proper organ function and tissue homeostasis. Consequently, blood vessel defects can lead to serious illnesses and contribute to stroke and cardiovascular disease. We are interested in identifying the genes that cause blood vessels to grow properly in developing embryos and how tree-shaped, hierarchically patterned blood vessel networks can arise. In particular, we are investigating how the forces exerted by the flowing blood influence the biology of individual cells that build blood vessel networks. We are also fascinated by the question of how different kinds of blood vessels, such as arteries and veins, arise. These are different in their makeup, and it is not understood which mechanisms might control their differentiation and subsequent maturation.
Research Focus
One fundamental aspect of growing blood vessels is the necessity to build functional networks, through which blood can flow from the heart into the body and back to the heart. The blood vessels that carry blood away from the heart are called arteries, while those returning the blood to the heart are called veins. Between arteries and veins lies a network of very small vessels known as capillaries. One research focus of our laboratory is to understand what factors guide the formation of arteries. We were able to directly visualize, using live imaging, the development of newly forming arteries during tissue regeneration in adult zebrafish. Here, we found that veins are the source of new arterial cells, and that some vein-derived cells exhibit specific migratory behaviors, enabling them to connect to pre-existing arteries. We also identified a chemokine receptor, cxcr4, that is important to coordinate these cell migration behaviors. In subsequent work, we investigated the signaling pathways controlling cxcr4 expression and found that Notch signaling is necessary to modulate cxcr4 expression and thereby influence cell migration. Our work has therefore helped to better understand how new arteries form and how arteries and veins can connect to each other appropriately.
In addition to their proper connectivity, newly forming blood vessels also need to acquire distinct sizes to allow for efficient blood flow patterns. Most vascular beds are arranged in a hierarchical manner, resembling the shape of trees. We study how these tree-shaped patterns can arise. We found that endothelial cells (the cells lining blood vessels) have very different shapes depending on the type of blood vessel they are building. Furthermore, these shapes were affected in a zebrafish mutant for the endoglin gene, a co-receptor for ligands of the bone morphogenetic protein pathway. Notably, endoglin mutations can cause a human disease condition known as hereditary hemorrhagic telangiectasia (HHT). Therefore, our studies not only shed light on blood vessel size control but might also provide the foundation for new HHT therapies.
Future Research Directions
We are currently investigating the molecules that control the sprouting of new veins, a process distinct from the one leading to the formation of new arteries. In the future, we also aim to understand the regulation of gene expression in response to the forces exerted by blood flow
on endothelial cells. The mechanism by which cells interpret these forces is not yet understood. To gain insights into this regulation, we are investigating the epigenetic changes that occur in response to hemodynamic forces and how these changes might control gene expression patterns. We are also focusing on identifying the transcription factors and their binding sites that are important for controlling gene expression downstream of biophysical forces, with the goal of mutating these binding sites in zebrafish. We anticipate that understanding these regulations will also aid in deciphering the mechanisms underlying human cardiovascular diseases, as many of the genomic changes associated with disease are believed to be located within regions that regulate gene expression.