Browsing by Author "Ragab, Basma"

Lymphedema is a progressive disease, resulting from abnormalities of the lymphatic system. It is characterized by swelling of one or more parts of the body, due to impaired lymph transport. Lymphedema has no definitive treatment and it can have serious effects on the patients' quality of life. However, the recent knowledge expansion of the molecular mechanisms regulating lymphangiogenesis provides new possibilities for the treatment of lymphedema. One of these mechanisms is the angiopoietin-TIE system. It has been shown recently that ANG2 is essential for the formation of lymphatic vasculature. Mice ANG2-deletion caused widespread lymphatic dysfunction, resulting in subcutaneous edema and chylous ascites. Lymphatic development is also regulated by TIE1 receptor, as its deletion in mice resulted in malformed jugular lymph sacs and severe edema. In this study, a model of autocrine TIE receptor activation has been established in endothelial cells to investigate the effect of the WT-ANG2 and four ANG2 mutants (T299M, N304K, C435S and R492Q) in TIE receptor phosphorylation and lymphedema. The role of these variants in direct cell adhesion has also been investigated in vitro using HeLa and lymphatic endothelial cells. The findings revealed that WT-ANG2 and soluble ANG2 variants induced both TIE2 and TIE1 activation in endothelial cells. We also found that N304K, C435S and R492Q mutants are secretion-deficients and retain the co-expressed WT-ANG2 inside the cells, causing a dominant negative effect in both TIE2 and TIE1 receptor activation which is likely associated with the lymphedema in the patients where the mutants were identified.