Role of ERK1/2 and Rho A/Rho kinase in PKC‐induced contractions in ovine cerebral arteries: A developmental study

Abstract

ObjectiveWe tested the hypotheses that developmental maturation is associated with significant alterations in PKC mechanisms in Ca2+‐independent vascular contraction. In fetal and adult ovine cerebral arteries, in response to PKC stimulation, we quantified both total and phosphorylated levels of several proteins and tension and intracellular [Ca2+]i.ResultsIn both adult and fetus, PDBu‐induced contractions were 65% and 25% of Kmax, respectively, and ERK1/2 inhibition by U‐0126 decreased these contractions 40%. The ROCK inhibitor Y‐27632, decreased the response 50% in fetus but not adult. In adult cerebral arteries, PDBu increased phosphorylation of ERK1/2, ERK1/2‐dependent CaDSer789, CPI‐17Thr38, but not Rho A. In contrast, in fetal cerebral arteries activated Rho A, but not CaDSer789 or CPI‐17Thr38. By co‐immunoprecipatation, in adult, but not fetal, cerebral arteries PDBu‐simulated interaction between PKCα andCPI‐17, and PKCα and caldesmon.ConclusionsIn cerebral arteries, maturation with increasing myofilament Ca2+ sensitivity by MLCP regulation is associated with a transition from a PKC‐ERK1/2, Rho A‐dependent pathway in the fetus to one of CaDSer789‐ and CPI‐17Thr38‐dependent phosphorylation and increased myofilament Ca2+ sensitivity in the adult. In the immature organism, these differing signaling pathways may be associated with dysregulation of cerebral blood flow. (USPHS HD 03708)