The Syndecan-4/Protein Kinase Cα Pathway Mediates Prostaglandin E2-induced Extracellular Regulated Kinase (ERK) Activation in Endothelial Cells and Angiogenesis in Vivo

Prostaglandin E-2 (PGE(2)) 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 PGE(2)-induced angiogenic response. We show that in the absence of proteoglycan syndecan-4 (Sdc4), PGE(2)-induced ERK activation is decreased significantly, as is endothelial cell migration and cord formation in a two-dimensional Matrigel assay. In vivo, PGE(2)-induced angiogenesis is reduced dramatically in Sdc4(-/-) mice. The mechanism was traced to Sdc4-dependent activation of protein kinase C alpha (PKC alpha). Transduction of an Sdc4 S183E mutant (a cytoplasmic domain mutation that blocks Sdc4-dependent PKC alpha activation) into Sdc4(-/-) endothelial cells was not able to rescue the loss of PGE(2)-induced ERK activation, whereas a transduction with full-length Sdc4 resulted in full rescue. Furthermore, PGE(2)-induced angiogenesis was also reduced in PKC alpha(-/-) mice. Taken together, these results demonstrate that PGE(2)-induced activation of angiogenesis is mediated via syndecan-4-dependent activation of PKC alpha.