Signaling of hypoxia-induced autonomous proliferation of endothelial cells.

SPECIFIC AIMSThe present study was designed to analyze the ability of endothelial cells to proliferate on transient exposure to hypoxia by an autonomous response mechanism, i.e., without influence of paracrine effectors such as VEGF. Existence of such an autonomous proliferative response has been identified in cell cultures, but its signaling mechanism is unknown. We investigated the roles of the MEK/MAPK pathway and of cytosolic Ca2+ in the signaling mechanism.PRINCIPAL FINDINGS1. Transient hypoxia or metabolic inhibition induce endothelial cell proliferationAfter serum-free incubation for 24 h, transient hypoxia for 1 h resulted in increased proliferation of endothelial cells, quantified after another 24 h normoxic serum-free postincubation period (Fig. 1⤻ ). This proliferative effect was accompanied by an increase in 3H-thymidine incorporation, which indicates increased DNA synthesis (not shown). Rotenone (10 μM), an inhibitor of complex I of the mitochondrial respiratory chain, mimicked the proliferat...