title: Extracellular signal-regulated kinases and contractile responses in ovine adult and fetal cerebral arteries.
abstract: 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.
authors.affiliation: Center for Perinatal Biology, Departments of Physiology and Pharmacology, and Obstetrics and Gynecology, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wen
authors.initials: W
authors.lastname: Long
authors.forename: Lubo
authors.initials: L
authors.lastname: Zhang
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002536:Cerebral Arteries / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D015151:Immunoblotting; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011247:Pregnancy; D012756:Sheep; D013268:Stimulation, Chemical
chemical_list: D000316:Adrenergic alpha-Agonists; D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; C113580:U 0126; D010656:Phenylephrine; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium