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(Hypertension. 1997;30:247-251.)
© 1997 American Heart Association, Inc.

Articles

Flow-Mediated Vasodilatation Is Enhanced in Normal Pregnancy but Reduced in Preeclampsia

Anna P. Cockell; ; Lucilla Poston

From the Fetal Health Research Group, United Medical and Dental Schools, Division of Obstetrics and Gynaecology, St Thomas' Hospital, London, UK.

Correspondence to Prof L. Poston, Fetal Health Research Group, Division of Obstetrics and Gynaecology, St Thomas' Hospital, London SE1 7EH, UK. E-mail l.poston{at}umds.ac.uk

	Abstract

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Abstract Endothelium-derived nitric oxide is proposed to play an important role in the lowering of peripheral vascular resistance in normal pregnancy. In women with preeclampsia, the function of the endothelium is compromised, and it is suggested that reduced nitric oxide synthesis may contribute to the elevation of blood pressure and activation of coagulation pathways. In this study, we have compared responses to increments of intraluminal flow, considered to be a physiological stimulus to nitric oxide release, in arteries from normotensive nonpregnant and pregnant women and women with preeclampsia. Small subcutaneous arteries from normotensive pregnant women showed substantial flow-induced relaxation, which was attenuated by the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (mean relaxation, 48.3±8.0% [absence of L-NAME] versus 19.2±10.6% [presence of L-NAME]), whereas those from nonpregnant women and women with preeclampsia demonstrated modest constriction (mean constriction, 10.1±7.3% and 1.2±7.2%, respectively). Shear stress, the frictional force that is the stimulus for flow responses, was calculated from parameters of flow, viscosity, and artery diameter. Arteries from pregnant women showed greater relaxation to shear than those from nonpregnant women or those with preeclampsia. We conclude that flow-induced shear stress is a potent stimulus to vasodilatation in arteries from pregnant women and that this mechanism may lead to a fall in peripheral vascular resistance in normal pregnancy. Failure of this flow-induced dilatation may contribute to the gestational hypertension of preeclampsia.

Key Words: flow • nitric oxide • preeclampsia • pregnancy • shear stress • resistance artery

	Introduction

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Normal pregnancy is associated with an unexplained fall in peripheral resistance, which is evident at as early as 5 weeks of gestation¹ and is manifested by a progressive fall in blood pressure in the first and second trimesters,² despite an increase in cardiac output.¹

Studies in pregnant animals demonstrate augmented NO synthesis, which may contribute to a fall in vascular resistance,^{3 4 5} and it is suggested that this may be the consequence of estrogen-induced upregulation of the endothelial constitutive isoform of NOS (NOS-III).⁶ To date, there is little evidence to prove that NO plays a similar role in human pregnancy. Studies from our laboratory have produced conflicting results: we have found similar responses to the endothelium-dependent vasodilator ACh in small subcutaneous arteries from pregnant and nonpregnant women,⁷ whereas arteries from pregnant women were more responsive to an alternative endothelium-dependent vasodilator, BK.⁸ Recently, in a similar investigation in human small omental arteries,⁹ in which responses to ACh and BK were also determined, there was no indication for greater NO-mediated relaxation in arteries from pregnant women, although increased synthesis of a novel endothelium-derived factor was proposed. Indirect support for a role of enhanced NO release in human pregnancy may be derived from the elevation of NOS-III activity, which has been described in platelets,¹⁰ and from an increase in the urinary excretion of cGMP.¹¹

Preeclampsia is associated with vasoconstriction in a number of maternal vascular beds and is increasingly recognized to be a syndrome characterized by profound dysfunction of the vascular endothelium.^{12 13} This has led to the suggestion that a lack of NO may contribute to the elevation of blood pressure and the coagulation disorders commonly associated with this disease. Indeed, in earlier studies, we have reported poor endothelium-dependent relaxation to both ACh and BK in isolated small arteries from women with preeclampsia.^{8 13}

In the present study of small arteries from nonpregnant women and pregnant women with and without preeclampsia, we have evaluated responses to flow-induced shear stress. Shear stress is the frictional force at the endothelial surface that results from intraluminal flow, and it is considered to be an important physiological stimulus to NO-mediated vasodilatation.¹⁴ Arteries were obtained from biopsies of subcutaneous fat and mounted on a pressure arteriograph. The responses to shear stress were evaluated by determining changes in vessel diameter in response to increasing intraluminal flow.

	Methods

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The present study was approved by the local ethical committee, and all women gave informed consent before surgery. Patient details are presented in the Table. Biopsies of subcutaneous fat were obtained at cesarean section in pregnant women and during abdominal gynecological surgery in the normotensive nonpregnant women. Diagnosis of preeclampsia was according to the criteria of Redman and Jefferies¹⁵ : an initial diastolic pressure measurement below 90 mm Hg, an increase of diastolic blood pressure by at least 25 mm Hg, and a maximum reading of at least 90 mm Hg. Proteinuria was assessed by dipstick analysis. All women were delivered within 12 to 18 hours of admission. Women with preeclampsia who had received ß-blockers, methyl-dopa, or calcium antagonists were excluded from the study. Women with a previous history of nongestational hypertension, diabetes, or systemic lupus erythematosus were also excluded from the study.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Subjects Studied

Flow Responses in Isolated Arteries
Arteries were dissected from the biopsies of subcutaneous fat and immediately mounted as described previously⁵ in a pressure arteriograph (Living Systems Instrumentation Inc). The vessels were orientated in the in vivo direction of flow on a pair of opposing glass microcannulas, previously matched for flow resistance.¹⁶ The organ bath was perfused (5 mL/min) with PSS (mmol/L: NaCl 119, KCl 4.7, CaCl₂ 2.5, MgSO₄ 1.17, NaHCO₃ 25, NaH₂PO₄ 1.18, EDTA 0.026, and glucose 5.5; pH 7.4, 37°C, gassed with 5% CO₂ in O₂). A servocontrolled pump maintained the required intraluminal pressure, and the internal diameter of the artery was recorded continuously using a video dimension analyzer.¹⁶ "In-line" pressure transducers monitored the proximal and distal pressure on each side of the artery, enabling calculation of the mean intraluminal pressure. Each artery was equilibrated for 30 minutes while pressurized to 40 mm Hg, and the baseline internal diameter was recorded. Viability of the artery was confirmed by exposure to extraluminal NE (10^–6 mol/L) in potassium-substituted PSS (64 mmol/L KCl in PSS); endothelial function, by relaxation to ACh (10^–6 mol/L). Any artery that failed to maintain pressure or that did not demonstrate occlusion of the lumen in response to NE or complete relaxation to ACh was excluded from the study. After stabilization (80 mm Hg, 10 minutes), NE, at a concentration sufficient to reduce the internal diameter by 45% to 50%, was added to the bath perfusate (10^-6 to 10^-7 mol/L, 20 minutes). Intraluminal flow was then initiated and increased at 5-minute intervals (0.00 to 1.46 µL/s), and the internal diameter was recorded at the end of each flow step. Inhibition of NOS was then induced by the addition of L-NAME (10^–4 mol/L) in the absence of flow or NE (15 minutes; pressure, 80 mm Hg), before constriction to NE in the continued presence of L-NAME (20 minutes). The flow protocol was then repeated. In additional experiments, the role played by cyclooxygenase products in flow-induced dilatation in arteries from normotensive pregnant women was investigated by the addition of indomethacin (10^–5 mol/L) for 35 minutes before the second flow response (in the absence of L-NAME). Previous studies from our laboratory have shown the flow response to be reproducible.⁵ In the present study, reproducibility of the flow response was ascertained in arteries from three normotensive pregnant women, in which the flow protocol was repeated in the absence of L-NAME or indomethacin. Wall shear stress (dyne/cm²) was calculated as 4xxQx10⁹/xr³, where is viscosity in poise (dyne/s/cm²) at 37°C (viscosity of PSS, 0.7 cp), Q is flow rate (µL/s), and r is artery radius (µm).

Statistical Analysis
Values are given as mean±SEM. Summary scores¹⁷ were calculated for each flow response and compared by parametric ANOVA, using Dunnett's correction for multiple comparisons with control when necessary (InStat GraphPad, GraphPad Software). Significance was assumed at P<.05.

	Results

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Diastolic blood pressure at delivery was significantly raised in the women with preeclampsia compared with those normotensive women delivered by cesarean section at term (Table). All women with preeclampsia had proteinuria, as assessed by dipstick analysis. There was no significant difference in gestational age between the pregnant groups or in age between the preeclamptic and normotensive pregnant women. Although the nonpregnant women were of reproductive age, they were significantly older than the pregnant women with or without preeclampsia.

Flow Responses
After equilibration at a pressure of 40 mm Hg, arteries from each group of women were of similar internal diameter (normotensive pregnant, 220±15 µm, n=20 patients; nonpregnant, 218±23 µm, n=10; and preeclampsia, 203±12 µm, n=6). Addition of NE before evaluation of flow responses led to the required reduction in internal diameter (45% to 50%) in all groups, although arteries from three women with preeclampsia required a lower concentration of NE to achieve this degree of constriction. Arteries from normotensive pregnant women (n=10) demonstrated a marked relaxation to flow, which at the maximum flow rate (1.46 µL/s) led to a 68±8% relaxation of initial NE-induced preconstriction equivalent to a 37±8% change in preconstricted internal diameter (Fig 1a). In contrast, flow did not lead to relaxation in arteries from the normotensive nonpregnant women (n=10) (Fig 1b) or the women with preeclampsia (Fig 1c). The flow response in both groups was significantly less than that in the normotensive pregnant women (normotensive pregnant versus nonpregnant, P<.01; normotensive pregnant versus preeclampsia, P<.01). In the absence of flow, L-NAME led to a small but nonsignificant potentiation of NE-induced tone in each group (percent reduction in NE-preconstricted internal diameter with L-NAME: normotensive pregnant, 6.1±6.6%, n=10; nonpregnant, 5.6±4.6%, n=10; and preeclampsia, 7.5±8.2%, n=6). In the arteries from the normotensive pregnant women, the second flow response in the presence of L-NAME (Fig 1a) was significantly blunted compared with the first response (percent relaxation of NE-induced preconstriction at maximum flow rate: normotensive pregnant, 68±8% before L-NAME versus 9±4% after L-NAME, n=10, P<.01). In the arteries from nonpregnant women and women with preeclampsia, the response in the presence of L-NAME was similar to that in the absence of the inhibitor (Fig 1b and 1c). Separate experiments, designed to evaluate the role played by cyclooxygenase products in flow-induced dilatation in arteries from normotensive pregnant women, showed a nonsignificant reduction in flow-induced relaxation with the cyclooxygenase inhibitor indomethacin (percent relaxation at maximum flow rate: 52±11% before indomethacin versus 36±9% after indomethacin, n=7, P=NS). The reproducibility of the flow response was demonstrated in three arteries from normotensive pregnant women in which the flow response was repeated in the absence of L-NAME or indomethacin (percent relaxation at maximum flow rate: 50±11% for first response versus 57±9% for second response in the absence of L-NAME, n=3, P=NS).

View larger version (11K): [in this window] [in a new window]   Figure 1. a and b, Percent change in NE-induced preconstriction in response to incremental increases in flow in isolated human subcutaneous arteries from normotensive pregnant women (n=10) (a) and normotensive nonpregnant women (n=10) (b). indicates the absence of L-NAME; , the presence of L-NAME. *P<.01 for pregnant vs pregnant with L-NAME; +P<.01 for pregnant vs nonpregnant without L-NAME. c, Percent change in NE-induced preconstriction in response to incremental increases in flow in isolated human subcutaneous arteries from women with preeclampsia (n=6). indicates the absence of L-NAME; , the presence of L-NAME. *P<.01 for preeclamptic without L-NAME vs normotensive pregnant without L-NAME.

The relationship between wall shear stress (calculated in each artery using the internal diameter immediately before the change in flow) and the change in internal diameter is shown in Fig 2. As anticipated, because of relaxation to flow, the range of shear stress values achieved in the arteries from the normotensive pregnant women (Fig 2a) in the absence of L-NAME (5±1 to 23±6 dyne/cm²) was considerably less than that from the arteries of the nonpregnant and normotensive pregnant women in the presence of L-NAME (Fig 2b) or of the women with preeclampsia (nonpregnant, 12±4 to 192±77 dyne/cm²; normotensive pregnant with L-NAME, 9±3 to 288±78 dyne/cm²; and preeclampsia, 15±5 to 106±27 dyne/cm², respectively). These data indicate that the arteries of the normotensive pregnant women have a quantitatively enhanced sensitivity to shear stress compared with those in all other groups (±L-NAME).

View larger version (12K): [in this window] [in a new window]   Figure 2. Shear stress–associated changes in NE-induced preconstriction in isolated human subcutaneous arteries from normotensive pregnant women in the absence of L-NAME (, n=10) and women with preeclampsia in the absence of L-NAME (, n=6) (a) and from normotensive pregnant women in the presence of L-NAME (, n=10) and normotensive nonpregnant women in the absence of L-NAME (, n=10) (b).

	Discussion

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In the present study, we have demonstrated that flow is a potent stimulus for vasodilatation in arteries from normotensive pregnant women but does not induce dilatation in arteries from nonpregnant women or in those from women with preeclampsia.

The lack of response to flow in the arteries from the nonpregnant women would appear to contradict the hypothesis that flow-induced relaxation is an important physiological mechanism in the control of peripheral vascular resistance in the nonpregnant state. Flow-induced dilatation has regularly been observed in conduit arteries¹⁸ and in some isolated vascular beds,¹⁹ but there are fewer reports in isolated resistance arteries. Significant dilatation has been observed in small rat cerebral²⁰ and gracilis²¹ arteries, although previous reports from our laboratory have documented minimal flow-induced dilatation in isolated resistance arteries from the mesenteric⁵ or skeletal muscle²² circulations of the nonpregnant rat. To our knowledge, there is no previous study of flow responses in isolated human small arteries, although investigations in vivo of human brachial artery responses to flow (induced by downstream hyperemia and assessed by high-resolution Doppler ultrasound) have shown modest dilatation in this conduit artery.²³ The absent response in the small arteries from the nonpregnant women in the present study could simply reflect a peculiarity of the subcutaneous circulation or absent responses in this size of artery. However, we have shown previously that these arteries dilate to ACh and BK.^{7 8} NO synthesis resulting from stimulation by intraluminal flow, ACh, or BK is achieved through similar effector mechanisms. In the nonpregnant state, therefore, it is possible that an element of the shear stress sensor mechanism is absent or attenuated. This mechanotransduction pathway has not been fully defined, although it may occur through the cytoskeletal proteins and by rearrangement of integrins on the basolateral membrane. The absent flow response in the arteries from nonpregnant women may also be a reflection of the dilator response being influenced by the initial degree of active tension. As this was not rigorously investigated, it is possible that an optimal degree of preconstriction was not achieved. Additional confounding factors could include the difference in age of the nonpregnant and pregnant women or the phase of the menstrual cycle during which the biopsies were sampled. A menstrual phase–related flow response is suggested by a previous study in normal women in which hyperemic-induced flow responses in the subcutaneous circulation were found to be greater during the follicular phase.²⁴ The routine lack of a flow response in all arteries from nonpregnant women in the present study would, nonetheless, suggest that these were not important considerations. These observations, together with the previous studies showing minimal responses in rat arteries,^{5 22} imply that flow-induced vasodilatation does not always occur in resistance arteries from nonpregnant animals and humans.

The striking contrast between the flow responses in the arteries isolated from the subcutaneous circulation of pregnant and nonpregnant women suggests the development of a sensitive shear stress–dependent mechanism of vasodilatation in pregnancy. In common with most reports of flow-induced relaxation,^{25 26} the relaxation in the arteries from the normotensive pregnant women was substantially mediated by release of NO, as the NOS inhibitor L-NAME significantly reduced the response. The contribution of NO to the vasodilatation in the arteries from the normotensive pregnant women is emphasized by the demonstration that in the presence of L-NAME, the response to increasing shear stress was remarkably similar to that in arteries from nonpregnant women. The addition of indomethacin led to a nonsignificant reduction in the flow response, suggesting that prostacyclin plays a little role, if any, in mediating dilatation in this experimental protocol. However, without the simultaneous addition of L-NAME and indomethacin to eliminate both prostacyclin and NO-mediated relaxation, it is not possible to draw a firm conclusion concerning the role of this prostanoid. Further experiments of this kind would indicate whether another factor, such as endothelium-derived hyperpolarizing factor,²⁷ may contribute to the residual relaxation observed in the presence of L-NAME.

We propose that enhanced flow-induced vasodilatation may be characteristic of the state of pregnancy, since we have identified very similar responses in small mesenteric arteries from pregnant rats, whereas those from virgin rats did not dilate to flow.⁵ We have also recently observed flow-induced vasodilatation in arteries from the human placenta²⁸ and pregnant myometrium.²⁹

The mechanism underlying the pregnancy-associated dilatation to shear stress must at present remain speculative. 17ß-Estradiol has been suggested to increase the activity of NOS in some³⁰ but not all³¹ reports and might therefore be expected to increase the tonic release of NO, but there was no indication of any basal increase in NO release in the arteries from the pregnant women, since, in the absence of flow, L-NAME reduced the internal diameters of arteries from pregnant and nonpregnant women to a similar extent. Alternatively, 17ß-estradiol could play a role in altering the sensitivity to shear stress, since we have recently shown that prolonged incubation of isolated mesenteric arteries from prepubertal female rats with 17ß-estradiol increased flow-induced relaxation³² but had no effect on basal NO release.

Endothelial dysfunction in preeclampsia, originally demonstrated by the measurement of a variety of serological markers³³ and, more recently, by functional studies in isolated resistance arteries,^{8 13 34} is now recognized as being central to the disease process. Theories proposed to account for endothelial damage include enhanced free radical synthesis³⁵ or the involvement of deported trophoblastic material.³⁶ The absence of flow-induced relaxation observed in the arteries from the women with preeclampsia emphasizes this pivotal role of the endothelium and suggests that a marked reduction in NO synthesis could contribute to intense vasoconstriction observed in many vascular beds of the maternal circulation.

In conclusion, we have demonstrated flow-induced dilatation in isolated arteries from normotensive pregnant women but not in arteries taken from nonpregnant women or those with preeclampsia. Enhanced responses to shear stress may therefore play an important role in the adaptation of the maternal circulation to pregnancy and, if absent in preeclampsia, could contribute to the elevation of the maternal blood pressure.

	Selected Abbreviations and Acronyms

 

ACh = acetylcholine BK = bradykinin L-NAME = N-nitro-L-arginine methyl ester NE = norepinephrine NO = nitric oxide NOS = NO synthase PSS = physiological saline solution

	Acknowledgments

 
This study was funded by Tommy's Campaign. We would like to thank the medical and midwifery staff on the Delivery Suite at St Thomas' Hospital for their help and cooperation during this study.

Received October 23, 1996; first decision November 13, 1996; accepted January 8, 1997.

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