Extracellular signal-regulated kinases and contractile responses in ovine adult and fetal cerebral arteries.

Accumulating evidence suggests that extracellular signal-regulated kinases (ERK1/2) play a key role in regulating vascular tone. To test the hypotheses that ERK1/2 modulate cerebral artery agonist-induced contraction, and that this changes with developmental age, we measured both total and phosphorylated ERK1/2 in adult and fetal ovine cerebral arteries. In middle cerebral arteries (MCA) we also examined tension and [Ca2+]i responses to phenylephrine (PHE), in the absence and presence of the ERK1/2 inhibitor U-0126 and the mitogen-activated protein kinase kinase (MAPKK or MEK) inhibitor PD-98059. In the fetus, but not adult, U-0126 potentiated PHE-induced contraction. In both age groups, inhibition by U-0126, but not PD-98059, decreased the PHE-induced [Ca2+]i increase; in fact for adult, this eliminated any significant [Ca2+]i increase. In turn in the adult, but not fetus, protein kinase C (PKC) inhibition by staurosporine (3 x 10(-8) M) prior to ERK1/2 inhibition by U-0126 (10(-5) M) prevented this elimination of [Ca2+]i increase. In adult and fetal cerebral arteries basal total ERK1/2 levels were similar. However, in fetal arteries the basal phosphorylated ERK1/2 levels were significantly less than in adult. In fetal, but not adult, cerebral arteries, 10(-6)-10(-4) M PHE increased ERK1/2 phosphorylation in a concentration- and time-dependent manner. The ERK1/2 inhibitor U-0126, but not the MEK inhibitor PD-98059, lowered basal activated ERK1/2 levels in vessels of both age groups. These results suggest that basal levels of phosphorylated ERK1/2 play an important role in suppressing Ca2+ sensitivity, perhaps by PKC inhibition. The developmental increase in cerebral artery basal phosphorylated ERK levels from fetus to adult, suggests a transition in the regulation of contraction from Ca2+ sensitivity in the fetal arteries to Ca2+ concentration in the adult vessels.