Vessel formation from mesodermal progenitors, vasculogenesis, is a fundamental process common to both embryonic development and certain pathophysiologies. Recently we showed that the formation of vascular cords from isolated clusters of angioblasts involves extensive invasive activity. During this process, vasculogenic sprouting, a group of endothelial cells invades hundreds of micrometers into avascular areas, and thereby lays down the structure of the primordial vascular plexus.
We aim to determine the specific role of fibronectin, and its major endothelial receptors in the process. Specifically, we will (1) determine if fibronectin acts as a guidance cue during vasculogenic sprouting, (2) study the cell-mediated macro- assembly dynamics and turnover of the transient, fibronectin-rich extracellular matrix surrounding the cords of primordial endothelial cells, (3) determine the molecular composition of cell adhesion complexes and the respective roles of integrins avb3 and a5b1, and (4) synthesize the experimental data into a quantitative model of vasculogenesis. Vasculogenic sprouting will be studied in vivo, through automated optical microscopy and a combination of fluorescence-tagged antibodies and GFP constructs, in the presence or absence of perturbing reagents. The long term goal of the project is to understand endothelial cell-ECM interactions in sufficient detail to allow the construction of predictive quantitative models, either for tissue engineering, or to understand developmental morphogenetic processes. Understanding blood vessel development is of overwhelming clinical importance. Our goal, and the goal of other vascular biologists, is to explain the mechanisms that promote or inhibit vessel growth and thus regulate the structure of the vessel network. In particular, endothelial progenitors are in the focus of therapeutic vascularization strategies, tissue engineering, and attempts to block tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087136-05
Application #
8019039
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2007-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
5
Fiscal Year
2011
Total Cost
$257,250
Indirect Cost
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Aleksandrova, Anastasiia; Czirok, Andras; Kosa, Edina et al. (2015) The endoderm and myocardium join forces to drive early heart tube assembly. Dev Biol 404:40-54
Aleksandrova, Anastasiia; Rongish, Brenda J; Little, Charles D et al. (2015) Active cell and ECM movements during development. Methods Mol Biol 1189:123-32
Czirók, András; Varga, Katalin; Méhes, El?d et al. (2013) Collective cell streams in epithelial monolayers depend on cell adhesion. New J Phys 15:
Czirok, Andras (2013) Endothelial cell motility, coordination and pattern formation during vasculogenesis. Wiley Interdiscip Rev Syst Biol Med 5:587-602
Czirok, Andras; Little, Charles D (2012) Pattern formation during vasculogenesis. Birth Defects Res C Embryo Today 96:153-62
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Aleksandrova, Anastasiia; Czirók, Andras; Szabó, Andras et al. (2012) Convective tissue movements play a major role in avian endocardial morphogenesis. Dev Biol 363:348-61
Sanchez, Nora S; Hill, Cynthia R; Love, Joseph D et al. (2011) The cytoplasmic domain of TGFýýR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior. Dev Biol 358:331-43
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Szabo, A; Rupp, P A; Rongish, B J et al. (2011) Extracellular matrix fluctuations during early embryogenesis. Phys Biol 8:045006

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