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

Department of Physiology and Pharmacology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California

Submitted 22 November 2005 ; accepted in final form 3 January 2006

	ABSTRACT

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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.

sheep; protein kinase C; extracellular signal-regulated kinase

Although arterial myogenic behavior has been studied intensively for decades, the mechanisms by which vascular smooth muscle cells respond to changes in intraluminal pressure are still not fully understood. Previous studies (17, 29, 37) indicated that myogenic tone was highly dependent on an elevation of intracellular free Ca²⁺ concentration ([Ca²⁺]_i). However, it has also been demonstrated that Ca²⁺ sensitization mechanisms contribute to myogenic tone (28, 30, 49, 50). Activation of various kinase cascades regulating Ca²⁺ sensitivity of the contractile apparatus may modulate the level of arteriolar myogenic reactivity (8, 21). PKC has been proposed to play an important role in the regulation of basal vascular tone and arterial caliber, the major determinants of blood flow (6, 41, 44). Pressure-induced activation of PKC has been proposed to induce myogenic tone without additional increases in Ca²⁺ concentrations or myosin light chain (MLC₂₀) phosphorylation (18, 31). Our recent studies have also demonstrated in ovine uterine arteries that activation of PKC causes sustained contractions in the absence of changes in [Ca²⁺]_i and MLC₂₀ phosphorylation levels (56) and that the PKC-mediated contraction is significantly attenuated in the uterine artery during pregnancy (58). However, the role of PKC in the regulation of uterine artery myogenic tone during pregnancy has not been defined.

In addition to PKC, ERK is involved in the regulation of essential cellular processes. However, conflicting results were obtained regarding the role of ERK in smooth muscle contractile regulation. Several studies (1, 13) have demonstrated that ERK plays a role in the regulation of smooth muscle contraction. In contrast, studies with the swine carotid artery showed that inhibition of MAPKK (MEK)/ERK with PD-098059 had no effect on agonists-mediated contraction (15). Our recent studies have demonstrated that ERK plays an important role in the regulation of uterine artery contractility, and its effect is agonist dependent. More importantly, pregnancy selectively enhances the role of ERK in ₁-adrenoceptor-mediated contractions and its effect in suppressing the PKC-mediated contraction in the uterine artery (55, 56, 58). ERK was shown to be phosphorylated and activated by mechanical stretch (4, 33), and inhibition of ERK activation resulted in a decrease of pressure-induced myogenic tone in rat cerebral arteries (35), rat gracilis muscle arterioles (27), and human coronary arterioles (24). It is not clear whether or to what extent ERK plays a role in the regulation of uterine artery myogenic tone and its adaptation to pregnancy.

In the present study, we investigated the effects of pregnancy on myogenic tone in the resistance-sized uterine arteries from sheep. We hypothesized that myogenic tone was attenuated in the resistance-sized uterine arteries during pregnancy, which was due to a decrease in Ca²⁺ sensitivity of the contractile process. We also investigated the role of PKC and ERK in the regulation of uterine artery myogenic tone and its adaptation to pregnancy.

	METHODS

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Vessel isolation and cannulation. Nonpregnant and pregnant (140 days gestation) sheep were anesthetized with thiamylal (10 mg/kg), administered via the external left jugular vein. The ewes were then intubated, and anesthesia was maintained on 1.5% to 2.0% halothane in O₂ throughout the surgery. An incision in the abdomen was made, and the uterus was exposed. The uterine arteries were isolated and removed without stretching and were placed into a cold physiological salt solution (PSS) containing (in mM) 130 NaCl, 10.0 HEPES, 6.0 glucose, 4.0 KCl, 4.0 NaHCO_3, 1.80 CaCl₂, 1.2 MgSO₄, 1.18 KH₂PO₄, and 0.025 EDTA (pH 7.4). After the tissues were removed, animals were killed with euthanasia solution (T-61, Hoechst-Roussel; Somervile, NJ). All procedures and protocols used in the present study were approved by the Animal Research Committee of Loma Linda University and followed the guidelines in the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.

Resistance-sized uterine artery segments (150 µm in diameter) were dissected and cannulated in an organ chamber (Living Systems, Burlington, VT), followed by placement on the stage of an inverted microscope. The proximal cannula was connected to a pressure transducer and reservoir of PSS, and the intraluminal pressure was controlled by a servo-system to set transmural pressures. The distal cannula was connected to a Luer-Lok valve that was open to flush the lumen during the initial cannulation. After cannulation, the valve was closed, and all measurements were conducted under no-flow conditions. Arterial diameter was recorded by the use of the SoftEdge Acquisition Subsystem (IonOptix, Milton, MA) as described previously (11, 12).

Measurement of myogenic tone. After being mounted, the vessels were equilibrated in PSS for 10 min at an intraluminal pressure of 20 mmHg, followed by an increasing of pressure from 20 to 70 mmHg and a returning to 20 mmHg immediately. The vessels were then allowed to equilibrate at 20 mmHg for another 30 min. After the equilibration period, the intraluminal pressure was reduced to 10 mmHg, and arterial segments were further stabilized for 10 min. The pressure was then increased in a stepwise manner from 10 to 100 mmHg in 10-mmHg increments, and each pressure was maintained for 5–10 min to allow vessel diameter to stabilize before measurement. The passive pressure-diameter relationship was conducted in Ca²⁺-free PSS containing 3 mM EGTA to determine the maximum passive diameter. The following formula was used to calculate percent myogenic tone at each pressure step: %myogenic tone = (D₁ – D₂)/D₁ x 100, where D₁ is the passive diameter in Ca²⁺-free PSS (zero Ca²⁺ with 3 mM EGTA) and D₂ is the active diameter with normal PSS in the presence of extracellular Ca²⁺.

Measurement of vascular smooth muscle [Ca²⁺]_i. [Ca²⁺]_i was measured in tissues loaded with fura-2 as previously described (11, 12). Arterial segments were cannulated and pressurized to 10 mmHg and equilibrated at 37°C for 30 min. The cannulated artery segments were incubated with 2.5 µM fura-2 AM in PSS at room temperature for 1 h, followed by a washout period of 30 min at 37°C to allow for hydrolysis of fura-2 ester groups by endogenous esterase. Fura-2 fluorescence was measured by using a photomultiplier system (IonOptix) with two alternative excitation wavelengths at 340 and 380 nm and the emission of 510 nm. The fluorescence intensity at each excitation wavelength (F₃₄₀ and F₃₈₀, respectively) and the ratio of these two fluorescence values (R_f340/380) were recorded simultaneously with arterial diameter measured with the use of the SoftEdge Acquisition Subsystem. Percent [Ca²⁺]_i (measured as fura-2; R_f340/380) at each pressure was determined in arteries as (Ca₁²⁺ – Ca₂²⁺)/ Ca₁²⁺ x 100, where Ca₁²⁺ is [Ca²⁺]_i obtained with normal PSS at given pressure and Ca₂²⁺ is [Ca²⁺]_i obtained with Ca²⁺-free PSS at the same pressure.

Chemicals. Fura-2 AM was purchased from Molecular Probes (Eugene, OR). All other chemicals were purchased from Sigma (St. Louis, MO).

Data analysis. Data were expressed as means ± SE. Differences were evaluated for statistical significance (P < 0.05) by repeated-measures, two-way ANOVA.

	RESULTS

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Effect of pregnancy on myogenic tone in pressurized uterine arteries. In the absence of extracellular Ca²⁺ with Ca²⁺-free PSS, the diameters of uterine arteries of nonpregnant and pregnant sheep at 0 mmHg were 150.5 ± 5.5 µm (n = 8) and 146.7 ± 7.1 µm (n = 10), respectively. As shown in Fig. 1, arterial passive diameters significantly increased in response to step increases of intraluminal pressure (10–100 mmHg), and the diameters of uterine arteries of pregnant sheep were significantly greater than those of nonpregnant sheep at each pressure step (P < 0.05). In the presence of extracellular Ca²⁺ with normal PSS, uterine arteries of both nonpregnant and pregnant sheep developed myogenic tone in response to step increases of intraluminal pressure. As shown in Fig. 2, myogenic tone was significantly reduced in uterine arteries of pregnant, compared with nonpregnant, sheep (P < 0.05).

View larger version (10K): [in this window] [in a new window]   Fig. 1. Effect of pressure on passive arterial diameter in uterine arteries of nonpregnant and pregnant sheep. Arterial diameter was measured in the Ca2+-free physiological salt solution with 3 mM EGTA at given pressures. Data are means ± SE of tissues from 8–10 animals of each group. *P < 0.05, significant difference between nonpregnant and pregnant groups, as determined by repeated-measures, two-way ANOVA.

View larger version (9K): [in this window] [in a new window]   Fig. 2. Effect of pressure on myogenic tone in uterine arteries of nonpregnant and pregnant sheep. Mygenic tone was calculated as percent difference between passive diameter and active diameter at given pressures, as described in METHODS. Data are means ± SE of tissues from 6 animals of each group. *P < 0.05, significant difference between nonpregnant and pregnant groups, as determined by repeated-measures, two-way ANOVA.

View larger version (8K): [in this window] [in a new window]   Fig. 3. Effect of pressure on intracellular Ca2+ concentration ([Ca2+]i) in uterine arteries of nonpregnant and pregnant sheep. [Ca2+]i in uterine artery was measured as fura-2 fluorescence ratio (Rf340/380) at given pressures. Percent changes of [Ca2+]i were calculated as described in METHODS. Data are means ± SE of tissues from 5–6 animals of each group.

View larger version (5K): [in this window] [in a new window]   Fig. 4. Effect of agonists and pressure on [Ca2+]i and vessel diameter in uterine arteries. Uterine arteries were loaded with fura-2 and pressurized at 20 mmHg. Arterial diameter and [Ca2+]i (fura-2 fluorescence ratio, Rf340/380) were measured simultaneously in the same tissues. Representative traces show the effect of KCl (120 mM; A), pressure (100 mmHg; B) and phorbol 12,13-dibutyrate (PDBu, 10 µM; C) on [Ca2+]i and arterial diameter of uterine arteries during pregnancy. The same results were obtained from at least three additional separate experiments of uterine arteries from both pregnant and nonpregnant sheep.

View larger version (9K): [in this window] [in a new window]   Fig. 5. Effect of pressure on Ca2+ sensitivity of myogenic tone in uterine arteries of nonpregnant and pregnant sheep. Uterine arteries were loaded with fura-2, and myogenic tone and [Ca2+]i (fura-2 fluorescence ratio, Rf340/380) were measured simultaneously in the same tissues at given pressures. Myogenic tone-to-[Ca2+]i ratio (Rf340/380) was determined as function of pressure. Data are means ± SE of tissues from 5–6 animals of each group. *P < 0.05, significant difference between nonpregnant and pregnant groups, as determined by repeated-measures, two-way ANOVA.

View larger version (11K): [in this window] [in a new window]   Fig. 6. Effect of PKC inhibitor on myogenic tone in uterine arteries of nonpregnant and pregnant sheep. Mygenic tone was determined in the absence or presence of PKC inhibitor calphostin C (0.3 µM for 20 min) at given pressures. Data are means ± SE of tissues from 5–6 animals of each group. *P < 0.05, significant differences between calphostin C-treated and nontreated groups, as determined by repeated-measures, two-way ANOVA.

View larger version (11K): [in this window] [in a new window]   Fig. 7. Effect of ERK inhibitor on myogenic tone in uterine arteries of nonpregnant (top) and pregnant (bottom) sheep. Mygenic tone was determined in the absence or presence of ERK inhibitor PD-098059 (30 µM for 20 min) at given pressures. Data are means ± SE of tissues from 5–6 animals of each group. *P < 0.05, significant differences between PD-098059-treated and nontreated groups, as determined by repeated-measures, two-way ANOVA.

	DISCUSSION

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Previous studies (16, 38, 39, 51) have shown a decrease in pressure-induced myogenic tone of uterine, mesenteric, and renal arteries in pregnant mice and rats. In contrast, myogenic reactivity of myoendometrial radial uterine arteries was found to be increased in pregnant rats (41). The present study clearly demonstrates that the pressure-induced myogenic response of uterine arteries was significantly decreased in pregnant, compared with nonpregnant, sheep. In addition, the pressure-induced increases in arterial passive diameters were significantly greater in uterine arteries during pregnancy, suggesting a significant increase in the distensibility of the uterine arteries. Similar findings were obtained in rat uteroplacental radial arteries and veins that were shown to be more distensible in the pregnant state (43, 45).

It is well known that Ca²⁺ plays a pivotal role in smooth muscle contraction and setting of the vascular tone (6). However, the exact mechanisms of Ca²⁺ in the regulation of vascular myogenic reactivity remain uncertain. In the present study, we demonstrated that the membrane depolarization with KCl resulted in an increase in [Ca²⁺]_i and a decrease in the vessel diameter in pressurized uterine arteries. In contrast, activation of PKC with PDBu caused a decrease in the vessel diameter without changing [Ca²⁺]_i. These findings suggest that both Ca²⁺-dependent and Ca²⁺-independent pathways are involved in the regulation of vascular tone development in the uterine artery, depending on agonists. The finding that increased pressure from 20 to 100 mmHg led to an initial increase in vessel diameter and Ca²⁺ signal, followed by a decrease in diameter with a constant steady-state level of Ca²⁺ signal, suggests that in addition to an elevation of [Ca²⁺]_i, the pressure-induced constriction is mediated by increased myofilamental Ca²⁺ sensitivity. Previous studies (25) have shown that extracellular Ca²⁺ is obligatory for basal tone in pressurized resistance arteries. An acute increase in intraluminal pressure causes an increase in wall tension or cell stretch that alters vascular smooth muscle cell membrane ion conductance and results in increased levels of [Ca²⁺]_i and activation of the contractile process (7, 17, 19, 36). However, it has also been demonstrated that transient increases in [Ca²⁺]_i are not obligatory for myogenic constriction (26). Other studies (8, 21) also raised the possibility that pressure activates Ca²⁺-independent pathways and/or pathways that increase the sensitivity of the contractile machinery to Ca²⁺ (8, 21). Our current finding supports the notion that both [Ca²⁺]_i and myofilamental Ca²⁺ sensitivity contribute to the pressure-induced myogenic response in the uterine artery. The pressure-induced increases in [Ca²⁺]_i in the present study were found not to be significantly different in the uterine arteries between pregnant and nonpregnant sheep, suggesting that the decreased myogenic tone in the uterine artery during pregnancy is not mediated by differences of intracellular Ca²⁺ concentrations but rather by changes in the Ca²⁺ sensitivity. This notion is supported by normalizing [Ca²⁺]_i and diameter to the zero extracellular Ca²⁺ responses and determining the myogenic tone/[Ca²⁺]_i relationship, i.e., Ca²⁺ sensitivity, in arteries from nonpregnant and pregnant sheep. The finding that for each pressure step uterine arteries during pregnancy developed less tone at given [Ca²⁺]_i, compared with those of nonpregnant sheep, indicates that pregnancy attenuates Ca²⁺ sensitivity of the uterine artery in response to pressure. Similar findings were obtained in previous studies (53, 59) of isometric tension of uterine arterial rings loaded with fura-2, in which the ₁-adrenoceptor-mediated tension/[Ca²⁺]_i relationship in uterine arteries during pregnancy was significantly suppressed.

The mechanisms of pregnancy-mediated decrease in Ca²⁺ sensitivity in response to intraluminal pressure in the uterine artery are not clear at present. It has been demonstrated that the PKC-dependent pathway modulates primarily the Ca²⁺ sensitivity of myogenic mechanism (2, 14, 26, 35, 44). In the present study, we found that inhibition of PKC by calphostin C eliminated the differences in myogenic tone in uterine arteries between nonpregnant and pregnant sheep, suggesting that the pregnancy-associated decrease in myogenic tone is primarily regulated through the PKC signal pathway. Our group's previous studies (58) demonstrated that the PKC inhibitor calphostin C, as well as staurosporine, inhibited agonist-induced PKC activity in the uterine artery. It has been demonstrated that pregnancy attenuates the PKC activity and decreases PKC-mediated contractions of the uterine artery (10, 34, 58, 60). In agreement with our group's previous studies (55, 56, 58, 60) of isometric contractions of the uterine artery, the present study demonstrated that activation of PKC by PDBu decreased the diameter of pressurized uterine arteries without increasing intracellular Ca²⁺ concentrations, indicating a key role of Ca²⁺ sensitization in PKC-mediated changes in vascular tone in the uterine artery. Different mechanisms have been implicated in PKC-induced Ca²⁺ sensitization of the vascular smooth muscle contractile process (22, 32, 48, 52). Inhibition of MLC phosphatase, resulting in an increase in MLC phosphorylation, is a potential mechanism for enhancing Ca²⁺ sensitivity of contractile process in vascular smooth muscle (46, 48). However, it has been demonstrated that pressure-induced activation of PKC maintains vascular tone without an increase in MLC phosphorylation (20, 31), suggesting a thin filament regulatory mechanism involved in PKC-induced vascular tone. This notion is supported by several other studies (22, 23, 40), including those of our own in the uterine artery (56, 60), demonstrating that PKC induces contractions in the absence of increased MLC phosphorylation.

The present finding that the MEK inhibitor PD-098059 had no effect on pressure-induced myogenic tone in uterine arteries of nonpregnant sheep but enhanced it in uterine arteries during pregnancy is intriguing. MEK is an upstream kinase that phosphorylates and activates ERK. Our group's previous studies (56, 58) demonstrated that PD-098059 inhibited phosphorylation and activation of ERK in the uterine artery. Taken together, the results suggest that 1) ERK has an inhibitory effect on myogenic response and 2) pregnancy upregulates the ERK signaling pathway in the uterine artery. In agreement with the present finding, previous studies demonstrated a significant increase in ERK2 protein levels and phosphorylation/activation in uterine artery smooth muscle (58) and endothelial cells (3, 9), respectively, in pregnant sheep. It has been demonstrated that ERK phosphorylation increases in arterioles exposed to pressure (35). In rabbit facial vessels, the ERK inhibitor PD-098059 inhibited ERK activation but did not affect myogenic tone (33). To our knowledge, it has not been reported previously that inhibition of ERK with PD-098059 increases myogenic tone in any vessels. Nevertheless, the present finding is consistent with our recent studies measuring isometric contractions, in which PD-098059 significantly increased PKC-mediated contractions in ovine uterine (55, 56, 58, 60) and cerebral (61) arteries in pregnant, but not nonpregnant, sheep. The present finding that PD-098059 increased pressure-induced myogenic tone of uterine arteries during pregnancy suggests a physiological significance of ERK in the increased uterine blood flow by suppressing the basal vascular tone during pregnancy. We speculate that increased ERK attenuates myogenic tone by suppressing the PKC signal pathway in uterine arteries during pregnancy. This is supported by the following evidence: 1) inhibition of PKC blocks pressure-induced myogenic response in the uterine arteries; 2) inhibition of ERK enhances myogenic tone in uterine arteries during pregnancy and eliminates the differences in uterine arteries between nonpregnant and pregnant sheep; and 3) inhibition of ERK enhances PKC-mediated contractions in uterine arteries during pregnancy and minimizes the differences in PKC-mediated contractions in uterine arteries between nonpregnant and pregnant sheep (58).

In summary, we have shown in the ovine uterine artery that pressure-induced myogenic tone is regulated through both Ca²⁺ mobilization and Ca²⁺ sensitivity of the contractile process. Pregnancy downregulates myogenic tone of the uterine artery. The reduced myogenic tone is mediated in part by an increase in the inhibitory effect of ERK and a decrease in the PKC signal pathway, which lead to a decrease in Ca²⁺ sensitivity of myogenic mechanism in the uterine artery during pregnancy. Given that myogenic tone plays an important role in the regulation of vascular resistance and blood flow to various organs, the decreased myogenic tone and the increased distensibility of resistance-sized uterine arteries are likely to contribute significantly to the adaptation of uterine vascular hemodynamics in pregnancy.

	GRANTS

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This work was supported in part by National Institutes of Health Grants HL-57787, HL-67745, and HD-31226 and by Loma Linda University School of Medicine. D. Xiao is a recipient of Postdoctoral Fellowship Award from The Regents of the University of California Tobacco-Related Disease Research Program (Award No. 14FT-0075).

	FOOTNOTES

 

Address for reprint requests and other correspondence: L. Zhang, Center for Perinatal Biology, Dept. of Physiology & Pharmacology, Loma Linda Univ., School of Medicine, Loma Linda, CA 92350 (e-mail: lzhang{at}llu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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