FIG. 12.

Schematic representation of pathways involved in NOR-1 upregulation by thrombin and VEGF (light lines) and hypoxia (bold lines) in endothelial cells. Thrombin and VEGF induce NOR-1 expression through a mechanism dependent on PAR-1 (protease-activated receptor-1) and VEGF receptor-2 (VEGFR-2/KDR), respectively, and multiple signaling pathways including cytosolic Ca²⁺, the activation of PKC, and MAPK pathways (both ERK1/2 and p38 MAPK) that lead to the downstream activation of CREB. VEGFR-2 can also activate Ras/Raf/MEK/ERK signaling. An increase in intracellular Ca²⁺ activates calcium/calmodulin-dependent kinases (Ca/CM). The potential cross talk among signaling pathways is indicated by dashed arrows. p90^RSK, p38 MAPK, and Ca/CM are kinases potentially involved in CREB phosphorylation in Ser-133 (36). The indicated cross talk mechanisms and kinases potentially involved in CREB phosphorylation have not been specifically analyzed in relation with NOR upregulation. Hypoxia increases intracellular Ca²⁺ concentration, which activates the PI3K/Akt pathway and its downstream target mTOR. The PI3K/Akt/mTOR pathway could mediate the upregulation of HIF-1α protein levels by decreasing HIF-1α degradation and/or increasing HIF-1α synthesis (19, 20). Agents that inhibit NOR-1 expression interfering signaling pathways are indicated (boxed). Arrows and T-bars indicate activation and inhibition, respectively. ATAP-2, anti-PAR-1 blocking antibody; DAG, diacylglycerol; IP₃, inositol-1,4,5-triphosphate; PLC, phospholipase C; PTX, pertussis toxin.