Syndecan-4/PKCα pathway mediates Prostaglandin E2-induced ERK activation in endothelial cells and angiogenesis in vivo.

The prostaglandin E2 (PGE2) is regarded as the main mediator of inflammatory symptoms. In addition, it also plays an important role in tumor growth and angiogenesis. In this study we examined the mechanism of PGE2-induced angiogenic response. We show that in the absence of proteoglycan syndecan-4 (Sdc4), PGE2-induced ERK activation is significantly decreased as is EC migration and cord formation in a 2D Matrigel assay. In vivo, PGE2-induced angiogenesis is dramatically reduced in Sdc4-/- mice. The mechanism was traced to Sdc4-dependent activation of PKCα: transduction of a Sdc4 Ser183Glu mutant (a cytoplasmic domain mutation that blocks Sdc4-dependent PKCα activation) into Sdc4-/- EC was not able to rescue the loss of PGE2-induced ERK activation while a transduction with full length Sdc4 resulted in full rescue. Furthermore, PGE2-induced angiogenesis was also reduced in PKCα-/- mice. Taken together, these results demonstrate that PGE2-induced activation of angiogenesis is mediated via syndecan-4-dependent activation of PKCα.