Vascular remodeling, i.e., the growth and/or enlargement of both blood and lymphatic vessels, is tightly associated with inflammatory diseases, such as chronic airway inflammation, rheumatoid arthritis, inflammatory bowl disease, and chronic inflammatory skin psoriasis. The lymphatic system collects extravasated fluid, macromolecules, and immune cells from tissues and returns them to the blood circulation. While VEGFR2 and its ligand VEGF-A functions as master regulators of vasculogenesis and angiogenesis, VEGFR3 is critical for lymphangiogenesis. These conclusions are based on observations in genetically modified mice for VEGFR3 and its ligands. VEGFR3 is expressed on the blood and lymphatic endothelium during development, and is restricted to the lymphatics in the adult. Extensive studies have thus far focused on the role of VEGFR3 in lymphangiogenesis during development, however the function, regulation and intracellular mediators of the VEGFR3-dependent pathways in pathologic formation of lymphatic vessels during diseases remain poorly characterized. Our recent studies have identified two critical intracellular mediators, AIP1 and Bmx, in regulating VEGFR3 expression and activity. Genetic deletion of AIP1, a Ras-GAP protein, delays developmental lymphangiogenesis in neonatal skin and mesentery, and mounts weaker VEGF-C-induced cornea lymphangiogenesis. Deletion of Bmx, a non-receptor tyrosine kinase, has no effect on developmental lymphangiogenesis but blunts pathological lymphangiogenesis in mouse models. Mechanistically, AIP1 and Bmx sequentially regulate different steps during the VEGFR3 activation. AIP1 constitutively binds to VEGFR3 and enhances VEGFR3 endocytosis and stability. Bmx is not expressed in developmental lymphatics but is induced in response to pathological stimuli such as ischemia, and associates with an active form of VEGFR3 to regulate its downstream signaling without an effect on receptor phosphorylation. I will report the most recent progress as to how AIP1 and Bmx coordinately regulate VEGFR3-dependent lymphangiogenesis.
The Role of Master Regulators in the Metabolic/Transcriptional Coupling in Breast Carcinomas
