Precise regulation of vascular integrity via endothelial cell-cell junctions is critical for cell adhesion, paracellular permeability, vascular growth as well as immune cell trafficking. Increased endothelial permeability and associated inflammation occur in a large number of diseases with different etiology including sepsis, acute respiratory distress syndrome, diabetes and cancer, among others. These diseases present a worldwide health problem as they are difficult to treat. We are focused on attempts to understand the molecular functions of the ANG-TIE signaling system in pathological conditions and in the regulation of normal vascular homeostasis, searching for therapeutic possibilities to modulate endothelial cell functions via the ANG-TIE pathway.
We have discovered a novel mechanism of how angiopoietins activate the TIE receptors specifically at endothelial cell-cell junctions and in cell-matrix contacts, mediating endothelial stability and migration, respectively. A soluble angiopoietin growth factor induces the formation of receptor complexes across the cell-cell junctions, while a matrix-bound angiopoeitin mediates TIE activation at cell-matrix contact sites.
Recently, we showed that blocking ANG2 using therapeutic antibodies reduces tumor growth, angiogenesis, lymphangiogenesis as well as tumor metastasis. Blocking ANG2 inhibited tumor cell homing to the lungs by improving the integrity of endothelial cell-cell junctions in pulmonary capillaries.