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Sumanas Lab

Research

Zebrafish helps identify genetic causes of vascular disease

Overview

Sumanas lab focuses on understanding molecular mechanisms that regulate blood vessel development and disease. We use zebrafish as a model organism due to embryo transparency and experimental accessibility. Our research includes studying transcriptional regulation during embryonic vasculogenesis and angiogenesis, as well as pathological vascular development such as tumor angiogenesis. We are also performing screens for novel potential regulators of vasculature formation followed by their characterization and functional studies. And finally, we are using zebrafish as a tool to identify genetic causes of different human vascular diseases including intracranial aneurysms and vascular malformations.


  • Identification of molecular mechanisms of vasculogenesis

    Molecular mechanisms of how vascular endothelial cells differentiate and form functional vasculature are still poorly understood. We have identified a novel population of vascular progenitors that can incorporate into established blood vessels in zebrafish embryos. This project is focused on identifying cellular and molecular mechanisms of this novel process. Ultimately our studies will facilitate development of novel clinical therapies aimed at vascular repair and regeneration.

  • Role of SHE and ABL signaling in vascular tubulogenesis

    Molecular and cellular mechamisms that regulate the formation and maintenance of vascular lumen, or tubulogenesis, are poorly understood. The proposed study investigates the functional role of an evolutionarily conserved novel adaptor protein Src homology 2 domain containing E (She)  and its interaction with Abelson (Abl) kinase signaling pathway in regulating vascular lumen size in zebrafish embryos and human vascular endothelial cells. We are also exploring the potential application of SHE as a tool to normalize vascular lumen size in human venous malformations. The acquired knowledge will promote development of new strategies aimed at treating vascular malformations as well as bioengineering new vessels for regenerative therapies.

  • Genetic causes of intracranial aneurysms

    Intracranial aneurysms can result in devastating hemorrhages yet their genetic causes are poorly understood. In collaboration with clinical colleagues, we have been using zebrafish model to test genetic variants identified in individuals with intracranial aneurysms. Zebrafish mutants in the top candidate gene, collagen COL22A1, display increased incidence of hemorrhages and vascular defects. We are studying the role of COL22A1 in vascular stability and are investigating the role of other candidate genes identified in affected individuals. Identification of genetic causes of intracranial aneurysms will facilitate the development of novel clinical therapies.

  • ETS transcription factors in vascular development

    We have previously identified an ETS transcription factor Etv2 as a key evolutionarily conserved regulator of vasculogenesis. Etv2 mutants lack vasculature and instead vascular progenitors differentiate as cardiomyocytes or muscle cells. We are using single-cell transcriptome profiling, in vivo confocal imaging and genetic and other molecular approaches to study how Etv2 and other ETS transcription factors induce transcriptional program that controls vascular development.

Selected Publications

Metikala, S., Warkala, M., Casie Chetty S., Chestnut, B., Rufin Florat D., Plender E., Nester O., Koenig A.L., Astrof, S., Sumanas, S. (2022) Intercalation of vascular progenitors into functional blood vessels represents a distinct mechanism of vascular growth. Dev Cell 57, 767-782.

Gurung, S., Resrepo, N.K., Chestnut B., Klimkaite, L., Sumanas, S. (2022) Single-cell transcriptomic analysis of vascular endothelial cells in zebrafish embryos. Sci Rep 12: 13065.   

Chestnut, B., Casie Chetty, S., Koenig, A.L., Sumanas, S. (2020) Single-cell transcriptomic analysis identifies the conversion of zebrafish Etv2-deficient vascular progenitors into skeletal muscle. Nat Commun 11: 2796.

Casie Chetty, S., Sumanas, S. (2020) Ets1 functions partially redundantly with Etv2 to promote embryonic vasculogenesis and angiogenesis in zebrafish. Dev Biol 465, 11-22.

Quynh, V. T., Leino, D., Mowery, S.A., Bredemeier, N.O., Lafontant, P.J., Lubert, A., Gurung, S., Farlow, J.L., Foroud, T.M., Broderick, J., Sumanas, S. (2018) Collagen COL22A1 Maintains Vascular Stability and Mutations in COL22A1 are Associated with Intracranial Aneurysms. Dis Mod Mech 11, dmm033654.

Davis, J.A., Koenig, A.L., Lubert, A., Chestnut, B., Liu, F., Desai, S.P., Winkler, T., Pociute, K., Choi, K., Sumanas, S. (2018) ETS transcription factor Etsrp / Etv2 is required for lymphangiogenesis and directly regulates vegfr3 / flt4 expression. Dev Biol 440, 40-52.

Baltrunaite, K., Craig, M.P., Palencia Desai, S., Chaturvedi, P., Pandey, R.N., Hegde, R.S., Sumanas, S. (2017) ETS transcription factors Etv2 and Fli1b are required for tumor angiogenesis. Angiogenesis 20, 307-323.

Palencia-Desai, S., Rost, M.S., Schumacher, J., Ton, Q.V., Craig, M.P., Baltrunaite, K., Koenig, A.L., Wang, J., Poss, K.D., Chi, N.C., Stainier, D.Y.R., Sumanas, S. (2015) Myocardium and BMP Signaling Are Required for Endocardial Differentiation. Development 142, 2304-2315.

Craig, M.P., Grajevskaja, V., Liao, H.-K., Balciuniene, J., Ekker, S.C., Park, J.-S., Essner, J.J., Balciunas, D., Sumanas, S. Etv2 and Fli1b function together as key regulators of vasculogenesis and angiogenesis. (2015) Arterioscl Thromb Vasc Biol 35, 865-76.

Kohli, V., Schumacher, J.A., Palencia-Desai, S., Rehn, K., Sumanas, S. (2013). Arterial and venous progenitors of the major axial vessels originate at distinct locations. Dev Cell 25, 196-206.