Signalling interactions between platelets and lymphatic endothelial cells, linked to lymphangiogenesis

Langan, Stacey Anne (2015). Signalling interactions between platelets and lymphatic endothelial cells, linked to lymphangiogenesis. University of Birmingham. Ph.D.

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Abstract

The platelet receptor CLEC-2 is the only known endogenous ligand for the transmembrane receptor podoplanin, which is expressed on lymphatic endothelial cells (LEC) as well as a number of other cell types. Both CLEC-2 and podoplanin are required for normal lymphangiogenesis as mouse embryos lacking either protein develop a phenotype in which blood is detected in the lymphatic vessels. This thesis examines the role of the podoplanin-CLEC-2 interaction in the migratory and tube-forming capabilities of LEC.

Addition of platelets or antibody-mediated podoplanin crosslinking both inhibited migration of LEC in transfilter migration assays in the presence, but not absence, of vascular endothelial growth factor (VEGF)-C. Similarly, platelets and podoplanin crosslinking reduced stability of LEC networks formed in co-cultures with fibroblasts. We also found that siRNA-mediated knockdown of podoplanin negated the pro-migratory effects of VEGF-C and VEGF-A. Furthermore, we obtained evidence that podoplanin signalling may involve RhoA and Rho-kinase, and that the effect of podoplanin might be linked to its phosphorylation by protein kinase A downstream of VEGF receptor signalling. These data suggest that the interaction of podoplanin and CLEC-2 prevents connection between blood and lymphatic vessels through reductions in LEC migration and stability of cell-cell interactions.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Nash, G. B. (Gerard B.)UNSPECIFIEDUNSPECIFIED
Watson, Steve P.UNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine, Centre for Cardiovascular Sciences
Funders: British Heart Foundation, Medical Research Council
Subjects: R Medicine > RB Pathology
R Medicine > RC Internal medicine
URI: http://etheses.bham.ac.uk/id/eprint/6037

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