My laboratory is focused on the biology of angiogenesis in the setting of cardiovascular illnesses. Regulation of new vessels growth is a tightly controlled process that integrates multiple stimulatory and inhibitory signals. This integration takes place in endothelial cells that are subjected to multiple influences. Among these are the effects of circulating angiogenic growth factors and inhibitor, interactions with circulating blood cells such as monocytes and signals from the surrounding extracellular matrix. The ability of endothelial cells to respond to these various stimuli and to initiate (or terminate) the program for new vessel growth is at the heart of angiogenesis. We are focused on two principal areas in this field: the role of endothelial cell surface proteoglycans, and especially, core protein syndecan-4 in integration of growth factor and extracellular matrix signaling to endothelial cells, and the role of inflammatory cells in mediation of angiogenic response.
Syndecan-4 is a heparan sulfate chains-carrying transmembrane protein that can binds various extracellular matrix components such as fibronectin and collagen as well as circulating heparin binding growth factors such as fibroblast growth factors (FGF) via its heparan sulfate chains. Once bound to a ligand, syndecan-4 undergoes oligomerization accompanied by the shift to the rafts domain of the plasma cell membrane. This is followed by syndecan (and its ligand) endocytosis and transcytosis to the apical region of the plasma cell membrane. Syndecan-4 is a PDZ-binding protein and its interactions with its PDZ partners play an important role in its endocytosis and signaling. This cascade triggers a number of signaling events including activation of PKC alpha, MAPK and Rho-GTPases. As a result, cell migration and proliferation is stimulated. Current efforts in the laboratory focus on unraveling mechanisms of syndecan-4 endocytosis and transcytosis and on molecular mechanisms involved in stimulation of cell migration.
The second major area of research is the role of inflammatory mediators in stimulation of angiogenic responses. Recently we have identified a monocyte-derived peptide, PR39 as a novel regulator of angiogenesis. The peptide acts by inhibiting proteasome-dependent degradation of the transcription factor HIF-1 alpha thereby activating the VEGF cascade. At the same time, it also increases expression of FGF receptors FGF-R1 and syndecan-4, thereby triggering the FGF cascade. As a result, robust angiogenesis ensues. Current studies in the lab are focused on understanding of PR39 signaling in endothelial cells and on elucidation of physiologic properties of this peptide.
