Biological consequences of endothelial cell signaling

Sammanfattning: Endothelial cells make up the inner lining of blood and lymphatic vessels, where they participate in functions vital to survival of the tissue; endothelial cells maintain vessel integrity, dynamically respond to the changing metabolic needs of tissues, and participate in many tissue-specific functions. Endothelial cells sense environmental cues which initiate signal transduction pathways that regulate behavior. Endothelial cell dysfunction is a feature of many diseases, such as cancer, atherosclerosis, and retinopathies and therefore knowledge of endothelial signal transduction pathways is important for designing therapies to treat these diseases.The receptor tyrosine kinase VEGFR2 is a master regulator of endothelial cell biology, regulating survival, growth, migration, angiogenesis and vessel permeability. VEGF stimulation of VEGFR2 results in phosphorylation of tyrosine residues in the receptor’s intracellular domain. The phosphorylation of Y949, Y1173, and Y1212 is known to initiate complex signaling pathways in endothelial cells, but it is still unclear how each individual phosphosite contributes to overall endothelial regulation. The scaffold protein palmdelphin has been found to be highly expressed in endothelial cells, though its role in endothelial biology is still unclear.In this thesis I present investigations of endothelial cell signaling pathways. In Paper I, we identify VEGFR2 pY1212 binding partners and use a mouse model to reveal the effect of abrogated Y1212 signaling in vivo. In Paper II, we investigate endothelial palmdelphin and establish that loss of palmdelphin in vitro and in vivo results in morphological changes for endothelial cells. Additionally, loss of palmdelphin leads to a misalignment of endothelial nuclei in response to flow, implicating palmdelpin in a mechanotransduction pathway. In Paper III, we use mouse models of proliferative retinopathy to demonstrate that loss of VEGFR2 Y949 signaling leads to a reduction or delay in neovascularization and a decrease in vessel leakage from pathological lesions.In summary, the investigation of endothelial cell signal transduction pathways can help us understand and unravel the complexities of vascular biology. Designing therapies which affect only a specific signaling axis has the potential to reduce side effects and optimize treatment.