Maturation and Differential Role of PKC Isoforms in Adrenergic, Serotonergic, and Phorbol Ester–Mediated Cerebral Artery Contractility

Abstract

Protein kinase C (PKC) is a major family of kinases, containing approximately a dozen isoforms. The relative roles of each of these isoforms with maturation and contractile responses remain unclear. Thus, we tested the hypothesis that with maturation there is differential activation of PKC isoforms in response to agonist stimulation. We used cerebral arteries from fetal (~140 days) and non‐pregnant adult sheep for arterial tension measurement in response to the agonists phenylephrine (PHE), serotonin (5‐HT), and phorbol 12,13‐dibutyrate (PDBu) stimulation in the presence of specific PKC isoform inhibitors. We quantified mRNA using real‐time PCR. In both fetal and adult cerebral arteries: PHE, 5‐HT, and PDBu induced contractile responses, and these were completely inhibited by pan‐PKC inhibitory peptides. In the fetus, PKCα played a significantly greater role in 5‐HT‐ and PHE‐ induced contractions, as compared to adult. Also, in the fetus, PKCβ had a significantly greater role in PHE‐ and PDBu‐ induced contraction. Despite the varying contractile effects, PCR indicate significantly higher levels of PKC α, β, and ε mRNA levels in adult cerebral vessels, as compared to fetus. Overall, our results demonstrate activation of different PKC isoforms during fetal and adult life, with different agonists, which may be involved in fine‐tuning cerebral vascular tone and blood flow. Supported by NIH Grant HD3807‐37 to LDL.