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.

Preview

Langan15PhD.pdf
PDF - Redacted Version
Download (5MB)

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):