Enhancement of migration by protein kinase Cα and inhibition of proliferation and cell cycle progression by protein kinase Cδ in capillary endothelial cells

Abstract

Activation of protein kinase C (PKC) induces angiogenesis, migration, and proliferation of endothelial cells (EC), but can also prevent growth factor-induced EC proliferation. To determine whether these disparate effects are mediated by substrates of individual PKC isoenzymes, PKCα and PKCδ were overexpressed in rat microvascular EC. Basal and stimulated migration were enhanced in PKCα EC compared with either PKCδ or control EC. Serum-induced growth of PKCδ EC was decreased, while that of PKCα cells was similar to control EC. Phorbol ester markedly inhibited PKCδ EC growth but enhanced growth of PKCα and control EC. To determine possible causes for this altered proliferation, the effect of PKCδ on adhesion, mitogen-activated protein kinase activity, and cell cycle progression was measured. Adherence of PKCδ EC to vitronectin was significantly enhanced. Serum-induced extracellular signal-regulated kinase-2 activity was increased equally in both PKCα and PKCδ EC above that of control, while extracellular signal-regulated kinase- 1 activity was similar in all EC. Cell cycle analysis suggested that PKCδ EC entered S phase inappropriately and were delayed in passage through S phase. Thus, PKCα may mediate some proangiogenic effects of PKC activation; conversely, PKCδ may direct antiangiogenic aspects of overall PKC activation, including slowing of the cell cycle progression.