ERK inhibition attenuates 5-HT-induced contractions in fetal and adult ovine carotid arteries.
Growth and differentiation-related pathways are much more active in immature than in mature, fully differentiated smooth muscle. Because mitogen-activated protein kinases (MAPK) are intimately involved with growth and differentiation, and the extracellular signal-regulated kinase (ERK) subfamily of MAPKs are involved in some contractile responses, the present studies examined the hypothesis that ERKs play an important and age-dependent role in smooth muscle contraction. The MAPK inhibitors PD098059 and UO126 both inhibited serotonin (5-HT) concentration-response relations more effectively in carotid arteries from term fetal lambs, than in corresponding arteries from mature non-pregnant adult sheep. This inhibition involved significant decreases in both the pD2 (adult: 2-fold; fetus: 4- to 15-fold) and the maximum efficacy (adult: 15-19%; fetus: 34-39%) of 5-HT. Accompanying this age-dependent effect on contraction, quantitative Western blot assays revealed that ERK1 and ERK2 abundances were 39% and 164% greater, respectively, in fetal than in adult carotid arteries. The abundance of the putative ERK target, caldesmon, however, was about 7-fold greater in adult than in fetal arteries. Together, the present results support the view that ERK abundance and activity is upregulated in fetal relative to adult arteries, and that one consequence of this upregulation is that the contribution of ERKs to contraction, at least that initiated by 5-HT2a receptors, is greater in fetal than adult carotid arteries. Whereas the phosphorylation mechanisms through which ERKs augment contraction remain uncertain and controversial, the present results suggest that emphasis should be shifted away from caldesmon and toward other critical contractile proteins, and how these proteins may contribute differently to development of agonist-induced contractile force in immature and mature arteries.
Pearce
W J
WJ
Center for Perinatal Biology, Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA. wpearce@som.llu.edu
Williams
J M
JM
Chang
M M
MM
Gerthoffer
W T
WT
D000367:Age Factors; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000196:embryology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D012756:Sheep
D002070:Butadienes; D002148:Calmodulin-Binding Proteins; D005419:Flavonoids; D009570:Nitriles; C113580:U 0126; D012701:Serotonin; D017346:Protein Serine-Threonine Kinases; D009219:Myosin-Light-Chain Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009218:Myosins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one