scholarly journals Chronic hypoxia increases pressure-dependent myogenic tone of the uterine artery in pregnant sheep: role of ERK/PKC pathway

2009 ◽  
Vol 296 (6) ◽  
pp. H1840-H1849 ◽  
Author(s):  
Katherine Chang ◽  
Daliao Xiao ◽  
Xiaohui Huang ◽  
Lawrence D. Longo ◽  
Lubo Zhang
Keyword(s):  
Uterine Artery ◽  
Chronic Hypoxia ◽  
Ex Vivo ◽  
Signal Pathway ◽  
Myogenic Tone ◽  
Uterine Blood Flow ◽  
Pregnant Sheep ◽  
Near Term ◽  
Do So

Chronic hypoxia during pregnancy has profound effects on uterine artery (UA) contractility and attenuates uterine blood flow. The present study tested the hypothesis that chronic hypoxia inhibits the pregnancy-induced reduction in pressure-dependent myogenic tone of resistance-sized UAs. UAs were isolated from nonpregnant ewes (NPUAs) and near-term pregnant ewes (PUAs) that had been maintained at sea level (∼300 m) or at high altitude (3,801 m) for 110 days. In normoxic animals, the pressure-dependent myogenic response was significantly attenuated in PUAs compared with NPUAs. Hypoxia significantly increased myogenic tone in PUAs and abolished its difference between PUAs and NPUAs. Consistently, there was a significant increase in PKC-mediated baseline Ca2+ sensitivity of PUAs in hypoxic animals. Hypoxia significantly increased phorbol 12,13-dibutyrate (PDBu)-induced contractions in PUAs but not in NPUAs. Whereas the inhibition of ERK1/2 by PD-98059 potentiated PDBu-mediated contractions of PUAs in normoxic animals, it failed to do so in hypoxic animals. Hypoxia decreased ERK1/2 expression in PUAs. PDBu induced membrane translocation of PKC-α and PKC-ε. Whereas there were no significant differences in PKC-α translocation among all groups, the translocation of PKC-ε was significantly enhanced in NPUAs compared with PUAs in normoxic animals, and hypoxia significantly increased PKC-ε translocation in PUAs. In the presence of PD-98059, there were no significant differences in PDBu-induced PKC-ε translocation among all groups. Treatment of PUAs isolated from normoxic animals with 10.5% O2 for 48 h ex vivo significantly increased PDBu-induced contractions and eliminated its difference between PUAs and NPUAs. The results suggest that hypoxia upregulates pressure-dependent myogenic tone through its direct effect in suppressing ERK1/2 activity and increasing the PKC signal pathway, leading to an increase in the Ca2+ sensitivity of the myogenic mechanism in the UA during pregnancy.

Pregnancy-induced changes in sheep uterine and carotid arteries

1985 ◽  
Vol 248 (5) ◽  
pp. H658-H665 ◽  
Author(s):  
K. K. Griendling ◽  
E. O. Fuller ◽  
R. H. Cox
Keyword(s):  
Uterine Artery ◽  
Carotid Arteries ◽  
Vascular Tissue ◽  
Iodoacetic Acid ◽  
Biochemical Properties ◽  
Dna And Rna ◽  
Pregnant Sheep ◽  
Near Term ◽  
Induced Changes ◽  
Water Contents

To characterize the effects of pregnancy on vascular tissue, intact segments of the uterine and carotid arteries were removed from nonpregnant and near-term pregnant sheep. Pressure-diameter relations were measured on isolated segments under activated (122 mM K+, 10(-4) M phenylephrine) and passive (0.1 mM Ca2+, 10(-5) M iodoacetic acid) conditions. DNA and RNA were determined spectrophotometrically. Collagen, elastin, and water contents were also measured. Pregnancy had no effect on either the mechanics or the biochemical properties of the carotid artery. However, there was a marked increase in internal radius in the uterine artery with pregnancy (0.060 +/- 0.016 vs. 0.198 +/- 0.019 cm). Active tangential stress increased, as did passive stiffness of the uterine artery. The collagen fraction decreased during pregnancy (57.2 +/- 2.4 vs. 45.7 +/- 2.2%), while elastin and RNA remained unchanged. A small decrease in DNA produced a significant increase in the RNA-to-DNA ratio. These data suggest that, in pregnancy, the uterine artery selectively undergoes a characteristic hypertrophy of its vascular smooth muscle.

Adaptation of uterine artery thick- and thin-filament regulatory pathways to pregnancy

2005 ◽  
Vol 288 (1) ◽  
pp. H142-H148 ◽  
Author(s):  
DaLiao Xiao ◽  
Lubo Zhang
Keyword(s):  
Uterine Artery ◽  
Thin Filament ◽  
Kinase Inhibitor ◽  
Isometric Tension ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Pathways ◽  
Uterine Arteries ◽  
Pregnant Sheep ◽  
Mitogen Activated Protein ◽  
Near Term

Little is known about the adaptation of uterine artery smooth muscle contractile mechanisms to pregnancy. The present study tested the hypothesis that pregnancy differentially regulates thick- and thin-filament regulatory pathways in uterine arteries. Isometric tension, intracellular free Ca2+ concentration, and phosphorylation of 20-kDa myosin light chain (MLC20) were measured simultaneously in uterine arteries isolated from nonpregnant and near-term (140 days gestation) pregnant sheep. Phenylephrine-mediated intracellular free Ca2+ concentration, MLC20 phosphorylation, and contraction tension were significantly increased in uterine arteries of pregnant compared with nonpregnant animals. In contrast, phenylephrine-mediated Ca2+ sensitivity of MLC20 phosphorylation was decreased in the uterine arteries of pregnant sheep. Simultaneous measurement of phenylephrine-stimulated tension and MLC20 phosphorylation in the same tissue indicated a decrease in MLC20 phosphorylation-independent contractions in the uterine arteries of pregnant sheep. In addition, activation of PKC produced significantly lower sustained contractions in uterine arteries of pregnant compared with nonpregnant animals in the absence of changes in MLC20 phosphorylation levels in either vessels. In uterine arteries of nonpregnant sheep, the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase inhibitor PD-098059 significantly increased phenylephrine-mediated, MLC20 phosphorylation-independent contractions. The results suggest that in uterine arteries, pregnancy upregulates α1-adrenoceptor-mediated Ca2+ mobilization and MLC20 phosphorylation. In contrast, pregnancy downregulates the Ca2+ sensitivity of myofilaments, which is mediated by both thick- and thin-filament pathways.

Effect of prostaglandin E2 on ovine maternal placental blood flow

1976 ◽  
Vol 231 (3) ◽  
pp. 754-759 ◽  
Author(s):  
JH Rankin ◽  
TM Phernetton
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Placental Transfer ◽  
Venous Catheter ◽  
Uterine Blood Flow ◽  
Blood Flows ◽  
Pregnant Sheep ◽  
Maternal Brain ◽  
Regional Blood Flows ◽  
Near Term

The effect of PGE2 on regional blood flows in the chronically catheterized near-term pregnant sheep was investigated using radioactive microspheres. The injection of 20 mug PGE2 per kilogram into the left ventricle of eight sheep resulted in no change in maternal brain and noncotyledonary uterine flow. The renal blood flow increased from 692 to 892 ml/min (P less than 0.004). The uterine blood flow decreased from 673 to 317 ml/min (P less than 0.001). The trium was bypassed by injecting 7 mug PGE2 per kilogram of sheep into a fetal venous catheter and permitting it to reach the placental vasculature after placental transfer. Eleven sets of observations were made in eight animals. We observed no change in the intrauterine pressure, maternal brain flow, and noncotyledonary uterine blood flow secondary to this procedure. The maternal renal blood flow changed from 592 to 669 ml/min (P less than 0.007). The uterine blood flow increased from 762 to 853 ml/min (P less than 0.02). The uterine vascular resistance decreased from 0.124 to 0.115 mmHg x min/ml (P less than 0.04). It was concluded that 1) PGE3 crosses the placenta quite readily, and 2) PGE3 causes dilatation of the maternal placental vascular bed.

scholarly journals Ryanodine receptor subtypes regulate Ca2+ sparks/spontaneous transient outward currents and myogenic tone of uterine arteries in pregnancy

2020 ◽  
Author(s):  
Rui Song ◽  
Xiang-Qun Hu ◽  
Monica Romero ◽  
Mark A Holguin ◽  
Whitney Kagabo ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Uterine Artery ◽  
Vascular Tone ◽  
Myogenic Tone ◽  
Receptor Subtypes ◽  
Α Subunit ◽  
Uterine Arteries ◽  
Outward Currents ◽  
Pregnant Sheep ◽  
Spontaneous Transient Outward Currents

Abstract Aims Our recent study demonstrated that increased Ca2+ sparks and spontaneous transient outward currents (STOCs) played an important role in uterine vascular tone and haemodynamic adaptation to pregnancy. The present study examined the role of ryanodine receptor (RyR) subtypes in regulating Ca2+ sparks/STOCs and myogenic tone in uterine arterial adaptation to pregnancy. Methods and results Uterine arteries isolated from non-pregnant and near-term pregnant sheep were used in the present study. Pregnancy increased the association of α and β1 subunits of large-conductance Ca2+-activated K+ (BKCa) channels and enhanced the co-localization of RyR1 and RyR2 with the β1 subunit in the uterine artery. In contrast, RyR3 was not co-localized with BKCa β1 subunit. Knockdown of RyR1 or RyR2 in uterine arteries of pregnant sheep downregulated the β1 but not α subunit of the BKCa channel and decreased the association of α and β1 subunits. Unlike RyR1 and RyR2, knockdown of RyR3 had no significant effect on either expression or association of BKCa subunits. In addition, knockdown of RyR1 or RyR2 significantly decreased Ca2+ spark frequency, suppressed STOCs frequency and amplitude, and increased pressure-dependent myogenic tone in uterine arteries of pregnant animals. RyR3 knockdown did not affect Ca2+ sparks/STOCs and myogenic tone in the uterine artery. Conclusion Together, the present study demonstrates a novel mechanistic paradigm of RyR subtypes in the regulation of Ca2+ sparks/STOCs and uterine vascular tone, providing new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.

Effects of chronic hypoxia on Ca2+ mobilization and Ca2+ sensitivity of myofilaments in uterine arteries

1998 ◽  
Vol 274 (1) ◽  
pp. H132-H138 ◽  
Author(s):  
Lubo Zhang ◽  
Daliao Xiao
Keyword(s):  
Smooth Muscle ◽  
Fluorescence Intensity ◽  
Uterine Artery ◽  
Chronic Hypoxia ◽  
Effective Concentration ◽  
Uterine Arteries ◽  
Agonist Stimulation ◽  
Pregnant Sheep ◽  
Half Maximal Effective Concentration ◽  
Intracellular Ca

The effect of chronic hypoxia on free intracellular Ca2+ concentration ([Ca2+]i) and Ca2+ sensitivity of myofilaments during agonist stimulation was examined in uterine arteries obtained from normoxic and chronically hypoxic pregnant sheep maintained at high altitude (3,820 m) for ∼110 days. Smooth muscle [Ca2+]iwas measured simultaneously with muscle contraction in the same intact tissue. Whereas both KCl and 5-HT increased [Ca2+]iand tension simultaneously in the uterine artery, 5-HT produced significantly greater contractile tension (in g) than KCl at a given amount of [Ca2+]ias indicated by the ratio of fura 2 fluorescence intensity induced by excitation at 340 nm to that induced at 380 nm (29.8 ± 6.9 vs. 16.9 ± 4.0, P < 0.05). Chronic hypoxia did not change KCl-induced contractions, nor did it affect KCl-mediated increases in [Ca2+]i. In contrast, chronic hypoxia significantly inhibited 5-HT-induced contractions and decreased the 5-HT-stimulated increase in [Ca2+]i(pD2 7.46 ± 0.18 → 6.86 ± 0.11, P < 0.05, where pD2 is −log half-maximal effective concentration) in uterine arteries. In addition, the slope (g tension/nM [Ca2+]i) of the 5-HT-mediated [Ca2+]i-tension relationship was significantly decreased in chronically hypoxic arteries (0.024 ± 0.002 → 0.013 ± 0.001, P < 0.01). The results suggest that chronic hypoxia suppresses agonist-mediated Ca2+ homeostasis in uterine arteries by inhibiting Ca2+mobilization and the agonist-enhanced Ca2+ sensitivity of myofilaments.

Upregulation of eNOS in pregnant ovine uterine arteries by chronic hypoxia

2001 ◽  
Vol 280 (2) ◽  
pp. H812-H820 ◽  
Author(s):  
Daliao Xiao ◽  
Ian M. Bird ◽  
Ronald R. Magness ◽  
Lawrence D. Longo ◽  
Lubo Zhang
Keyword(s):  
Uterine Artery ◽  
Chronic Hypoxia ◽  
Enos Gene ◽  
Ionophore A23187 ◽  
Mrna Levels ◽  
Uterine Arteries ◽  
Pregnant Sheep ◽  
No Release ◽  
Endothelium Dependent Relaxation ◽  
Enos Protein

We tested the hypothesis that chronic high-altitude (3,820 m) hypoxia during pregnancy was associated with the upregulation of endothelial nitric oxide (NO) synthase (eNOS) protein and mRNA in ovine uterine artery endothelium and enhanced endothelium-dependent relaxation. In pregnant sheep, norepinephrine-induced dose-dependent contractions were increased by removal of the endothelium in both control and hypoxic uterine arteries. The increment was significantly higher in hypoxic tissues. The calcium ionophore A23187 -induced relaxation of the uterine artery was significantly enhanced in hypoxic compared with control tissues. However, sodium nitroprusside- and 8-bromoguanosine 3′,5′-cyclic monophosphate-induced relaxations were not changed. Accordingly, chronic hypoxia significantly increased basal and A23187 -induced NO release. Chronic hypoxia increased eNOS protein and mRNA levels in the endothelium from uterine but not femoral or renal arteries. In nonpregnant animals, chronic hypoxia increased eNOS mRNA in uterine artery endothelium but had no effects on eNOS protein, NO release, or endothelium-dependent relaxation. Chronic hypoxia selectively augments pregnancy-associated upregulation of eNOS gene expression and endothelium-dependent relaxation of the uterine artery.

scholarly journals Erratum: Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep

Gene Therapy ◽  
2008 ◽  
Vol 15 (20) ◽  
pp. 1410-1410
Author(s):  
A L David ◽  
B Torondel ◽  
I Zachary ◽  
V Wigley ◽  
K Abi-Nader ◽  
...  
Keyword(s):  
Blood Flow ◽  
Uterine Artery ◽  
Local Delivery ◽  
Uterine Blood Flow ◽  
Pregnant Sheep

scholarly journals Pregnancy attenuates uterine artery pressure-dependent vascular tone: role of PKC/ERK pathway

2006 ◽  
Vol 290 (6) ◽  
pp. H2337-H2343 ◽  
Author(s):  
DaLiao Xiao ◽  
John N. Buchholz ◽  
Lubo Zhang
Keyword(s):  
Uterine Artery ◽  
Vascular Tone ◽  
Mek Inhibitor ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Uterine Arteries ◽  
Intracellular Ca ◽  
Myogenic Responses ◽  
The Difference ◽  
Near Term

The mechanisms of adaptation of uterine artery vascular tone to pregnancy are not fully understood. The present study tested the hypothesis that pregnancy decreases the PKC-mediated Ca2+ sensitivity of the contractile process and attenuates myogenic tone in resistance-sized uterine arteries. In pressurized uterine arteries from nonpregnant (NPUA) and near-term pregnant (PUA) sheep, we measured, simultaneously in the same tissue, vascular diameter and vessel wall intracellular Ca2+ concentration ([Ca2+]i) as a function of intraluminal pressure. In both NPUA and PUA, membrane depolarization with KCl caused a rapid increase in [Ca2+]i and a decrease in diameter. A pressure increase from 20 to 100 mmHg resulted in a transient increase in diameter that was associated with an increase in [Ca2+]i, followed by myogenic contractions in the absence of further changes in [Ca2+]i. In addition, activation of PKC by phorbol 12,13-dibutyrate induced a decrease in diameter in the absence of changes in [Ca2+]i. Pressure-dependent myogenic responses were significantly decreased in PUA compared with NPUA. However, pressure-induced increases in [Ca2+]i were not significantly different between PUA and NPUA. The ratio of changes in diameter to changes in [Ca2+]i was significantly greater for pressure-induced contraction of NPUA than that of PUA. Inhibition of PKC by calphostin C significantly attenuated the pressure-induced vascular tone and eliminated the difference of myogenic responses between NPUA and PUA. In contrast, the MAPKK (MEK) inhibitor PD-098059 had no effect on NPUA but significantly enhanced myogenic responses of PUA. In the presence of PD-098059, there was no difference in pressure-induced myogenic responses between NPUA and PUA. The results suggest that pregnancy downregulates pressure-dependent myogenic tone of the uterine artery, which is partly due to increased MEK/ERK activity and decreased PKC signal pathway leading to a decrease in Ca2+ sensitivity of myogenic mechanism in the uterine artery during pregnancy.

scholarly journals Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep

Gene Therapy ◽  
2008 ◽  
Vol 15 (19) ◽  
pp. 1344-1350 ◽  
Author(s):  
A L David ◽  
B Torondel ◽  
I Zachary ◽  
V Wigley ◽  
K A Nader ◽  
...  
Keyword(s):  
Blood Flow ◽  
Uterine Artery ◽  
Local Delivery ◽  
Uterine Blood Flow ◽  
Pregnant Sheep
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