Enhancement of migration by protein kinase C alpha and inhibition of proliferation and cell cycle progression by protein kinase C delta in capillary endothelial cells

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