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Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK

(Requests for offprints should be addressed to P W F Hadoke, Endocrinology Unit, 2nd Floor O.P.D., Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK; Email: phadoke{at}staffmail.ed.ac.uk)

(R S Lindsay is currently at BHF Cardiovascular Research Centre, University of Glasgow, Gardiner Institute, 44 Church Street, Glasgow G12 6NT, UK)

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Excessive exposure to glucocorticoids during gestation reduces birth weight and induces permanent hypertension in adulthood. The mechanisms underlying this programmed elevation of blood pressure have not been established. We hypothesised that prenatal glucocorticoid exposure may lead to vascular dysfunction in adulthood. Pregnant rats received dexamethasone (Dex) (100 µg/kg, s.c.) or vehicle (control) daily throughout pregnancy. Blood pressure was elevated (students t-test, unpaired; P < 0.05) in adult female offspring (aged 12–16 weeks) of Dex-treated mothers (148.0 ± 3.6 mmHg, n=10) compared with the control group (138.0 ± 2.5 mmHg, n=8). Vascular responsiveness in aortae and mesenteric arteries was differentially affected by prenatal Dex: aortae were less responsive to angiotensin II, whereas mesenteric arteries were more responsive to norepinephrine, vasopressin and potassium (mesenteric arteries respond poorly to angiotensin II in vitro). Acetylcholine-mediated, endothelium-dependent relaxation was similar in both groups. Prenatal exposure to Dex had no effect on blood pressure or aldosterone response to acute (15 min, i.v.) infusion of angiotensin II (75 ng/kg per min). In contrast, chronic (2-week, s.c.) infusion of angiotensin II (100 ng/kg per min) produced a greater elevation (P < 0.05) of blood pressure in Dex-treated rats (150.0 ± 3.6 mmHg) than in controls (135.3 ± 5.4 mmHg), and aldosterone levels were higher in Dex-treated animals. There was no angiotensin II-induced medial hypertrophy/hyperplasia in mesenteric arteries from Dex-treated rats. These results indicate that vascular function is altered in a region-specific manner in rats with glucocorticoid-programmed hypertension. Despite a striking increase in mesenteric artery contraction in Dex-treated rats, in vivo studies suggest that abnormalities of the renin-angiotensin-aldosterone system, rather than enhanced vascular contractility, may be responsible for the elevation of blood pressure in these animals.

	Introduction

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Prenatal ‘programming’ of physiological responses (Barker et al. 1993), which could explain the association of low birth weight with increased risk of cardiovascular and metabolic disease in adulthood (Barker et al. 1990), has been attributed to several factors, including dietary modification (Langley-Evans et al. 1994, Woodall et al. 1996) and maternal stress during pregnancy (Lesage et al. 2001). Excess exposure of the foetus to glucocorticoids may provide a common mechanism for the programming response (Edwards et al. 1993). Indeed, in rats, maternal undernutrition produces a rise in maternal cortisol (Fowden 1995) and impaired glucocorticoid inactivation in the placenta (Langley-Evans et al. 1996, Nyirenda & Seckl 1998, Lesage et al. 2001). Furthermore, the link between glucocorticoids and adult hypertension is well established, with prenatal glucocorticoid administration (to rats and sheep) inducing low birth weight, impaired glucose tolerance and elevated blood pressure in adult offspring (Benediktsson et al. 1993, Lindsay et al. 1996, Dodic et al. 1998).

The mechanisms by which prenatal programming induces adult hypertension have not been established. One possibility is that changes in peripheral vascular function contribute to elevation of blood pressure; indeed, enhanced contractility has been demonstrated in femoral arteries isolated from rats exposed to maternal dietary restriction (Ozaki et al. 2001). Glucocorticoids could be implicated in programming of vascular function since they alter the function of both endothelial (Johns et al. 2001) and vascular smooth muscle cells (Ullian et al. 1996, Souness et al. 2002). Consequently, infusion of the synthetic glucocorticoid betamethasone elevates blood pressure and alters vascular contractile and dilator function in preterm lambs (Gao et al. 1996, Anwar et al. 1999, Docherty et al. 2001). The effects of these interactions may extend into later life as prenatal exposure results in permanent changes, such as elevated glucocorticoid receptor expression in adult rats (Nyirenda et al. 1998), in glucocorticoid signalling pathways.

We tested the hypothesis that prenatal exposure to glucocorticoids in rats results in altered vascular function in adult offspring. We used an established model of glucocorticoid-mediated, programmed hypertension (Benediktsson et al. 1993) to determine whether exposure to the synthetic glucocorticoid dexamethasone (Dex) in utero produced: 1) altered contractile and relaxant function in isolated (conduit and resistance) arteries in vitro and 2) altered vasopressor response in vivo. We investigated only female offspring, as recent studies (Khan et al. 2003, Ortiz et al. 2003) and our own experience (O’Regan et al. 2004) suggest that females are more likely to develop hypertension in response to prenatal programming.

	Materials and Methods

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Rats

As in previous studies, female Wistar rats (200–250 g; n=26) received daily s.c. injections of Dex (100 µg/kg; n=14) or vehicle (0.1 ml 4% ethanol-saline n=12) throughout pregnancy (Benediktsson et al. 1993). The number of pups per litter (16 ± 0.6 pups from saline-treated mothers) was reduced (P < 0.02) by prenatal Dex (13 ± 0.9 pups from Dex-treated mothers), but the ratio of males to females was unaffected. This was accompanied by a reduction (P < 0.01) in pup weight (3.77 ± 0.03 g in the saline group vs 3.36 ± 0.05 g in the Dex group): weight reduction was seen in both male and female pups. No death was observed in either group, litters were culled to eight pups and animals were randomly selected from different litters for subsequent experimentation. Stage of cycle was not taken into account at the time that measurements were made. Experiments conformed to The Principles of Animal Care (NIH publication no. 85–23, revised 1985) and were performed under the UK Home Office Animals (Scientific Procedures) Act 1986.

Materials

Salts were obtained from BDH, Poole, Dorset, UK; norepinephrine hydrochloride (NE), angiotensin (Ang) II, arginine vasopressin (AVP) and acetylcholine chloride (ACh), from Sigma.

Influence of prenatal Dex on vascular function in vitro

Blood pressure was measured in adult female (16 weeks) offspring by tail cuff plethysmography (Evans et al. 1994), on four different days, by an operator blinded to treatment.

Rats were killed by decapitation. Functional assessment of aortae and mesenteric arteries was performed by standard organ bath (Martin et al. 1986) and small-vessel myograph (Falloon et al. 1995) techniques respectively. Isometric force was measured in vessels suspended in physiological salt solutions (PSS) at 37 °C, perfused with carbogen. The arteries were equilibrated at their optimum resting settings (2.0 g (Martin et al. 1986) and 0.9 L100 (Falloon et al. 1995)) and subjected to a standard start procedure (Martin et al. 1986, Falloon et al. 1995).

Protocol  Cumulative concentration-response curves were obtained with NE (10^–9–3 x 10^–6 mol/l for aortae; 10^–9–310^–5 mol/l for mesenteric artery), potassium (KCl; 2.5x10^–3–3.2 mol/l for aortae; high-potassium PSS (KPSS), 2.5 x 10^–3–0.125 mol/l for mesenteric arteries), Ang II (10^–11– 1 x 10^–6 mol/l) and AVP (10^–11 –1x 10^–6 mol/l). Responses to the endothelium-dependent vasodilator ACh (10^–9–3 x10^–5 mol/l), were obtained after contraction with sufficient NE (3 x 10^–8–10^–5 mol/l) to achieve ~80% of the maximum contraction.

Influence of prenatal Dex on the pressor response in vivo

Acute  Three days prior to infusion, cannulae were inserted, under halothane anaesthesia (Fluothane, Zeneca, UK), into the carotid artery of adult (12 weeks), female pups (Benediktsson et al. 1993). Blood pressure was measured directly in conscious, unrestrained rats with the Elcomatic pressure transducer (Glasgow, UK) prior to, and during, venous infusion of Ang II (75 ng/kg per min for 15 min) (Brown et al. 1981). Blood samples were taken for measurement of plasma aldosterone.

Chronic  Blood pressure was measured in adult (12 weeks), female offspring by tail cuff plethysmography (Evans et al. 1994) on three separate days. Minipumps (Model 2002; Alzet, Cupertino, CA, USA) were implanted, under halothane anaesthesia, to infuse Ang II (Hypertensin; Ciba Geigy, Basel, Switzerland), 100 ng/kg per min, or vehicle s.c. for 2 weeks. Rats were killed by decapitation, trunk blood was collected for measurement of hormones, sections of the mesenteric arcade were fixed in 10% neutral buffered formalin for histological analysis, and tissues were retrieved and weighed.

Hormone assays

Plasma renin activity was measured as Ang I generated from plasma incubated at 37 °C for 30 min (Miller et al. 1980). Ang I, corticosterone (Kenyon et al. 1993) and aldosterone (DPC, Los Angeles, CA, USA) concentrations were measured by RIA.

Histological analysis

Fixed vessels were embedded in paraffin wax and 3 µm sections stained with elastic van Giessen. Image analysis was performed by an operator blinded to treatment, using MCID-M4 software (Imaging Research Inc, Brock University, St. Catherines, Ontario, Canada).

Statistics

Values are mean ± S.E.M for n pups from different mothers with the exception of in vivo data, where n refers to number of pups from five vehicle-treated and four Dex-treated mothers. Data were analysed by two-way, one-way or repeated-measures ANOVA with Tukey’s multiple-comparisons test or Student’s t-test, as appropriate. Significance was set at P < 0.05.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Influence of prenatal Dex on vascular function in vitro

At 16 weeks of age, female pups exposed to Dex in utero had elevated systolic blood pressure (control 138.0 ± 2.5 mmHg, n=8; Dex 148.0 ± 3.6 mmHg, n=10; P < 0.05).

Aorta

The sensitivity of aortic rings to Ang II was reduced by prenatal Dex exposure. A similar magnitude reduction in sensitivity to NE did not achieve significance (P=0.07) (Table 1). Maximum contractions and endothelium-dependent relaxation were unaffected by prenatal exposure to Dex (Fig. 1; Table 1).

View larger version (29K): [in this window] [in a new window]   Figure 1 The influence of prenatal Dex on contractile responses of aortae and mesenteric arteries taken from adult offspring. Prenatal exposure to Dex had no effect on aortic contraction (a–c), but enhanced contractile responses to (d) norepinephrine, (e) arginine vasopressin and (f) KCl in mesenteric arteries (: Dex, n = 8; : control, n = 4–6). Each point represents mean ± S.E.M. Curves were compared by two-way ANOVA.

Mesenteric arteries from control and Dex groups were similar in size (internal diameter 282 ± 14 µm (n=6) and 274 ± 17 µm (n=8) respectively; P=0.74). Contractile responses to NE, KCl and AVP were enhanced in mesenteric arteries from the Dex group (Fig. 1; Table 2). The sensitivity of the mesenteric artery to AVP (Table 2) was unaffected by prenatal Dex treatment (P=0.06). Ang II produced virtually no contraction in arteries from the Dex group and an unreproducible, spasmodic response in controls (data not shown). ACh-mediated relaxation of mesenteric arteries was unaffected by prenatal exposure to Dex (Table 2).

Acute pressor response  The elevation of basal blood pressure measured by carotid cannulation in Dex-exposed pups was again apparent (Table 3). In both groups of rats, Ang II infusion resulted in an acute rise in blood pressure evident a few seconds after the onset of the infusion (Table 3: ANOVA, P < 0.01). There was no difference, however, in the incremental rise in blood pressure in response to Ang II (control 18.5 ± 6.2 mmHg, n=6, Dex 16.5 ± 1.7 mmHg, n=5).

Chronic pressor response  Immediately before starting treatment of 12-week-old pups, mean arterial pressure was higher in the Dex group (control 118.9 ± 1.4 mmHg, n=16; Dex 123.4 ± 1.9 mmHg, n=16; P=0.05). After 7-day treatment with Ang II, blood pressure had increased in both groups (P < 0.01) (Fig. 2). The Dex/Ang II group had a higher blood pressure than the control/Ang II group (150.0 ± 3.6 mmHg, n=8 and 135.3 ± 5.4 mmHg, n=8; P < 0.05). The increment in blood pressure compared with pretreatment values (Fig. 2 inset) was greater in prenatal Dex-exposed rats, indicating that they were more sensitive to Ang II than the control group (P < 0.04).

View larger version (18K): [in this window] [in a new window]   Figure 2 Serial blood pressures before (dotted lines) and after (solid lines) treatment with Ang II in adult rats exposed to dexamethasone (Dex: •/, n = 8), or vehicle (control: /, n = 8), in utero. Repeated-measures ANOVA indicates that blood pressure was significantly higher in animals treated with Dex in utero (P < 0.05). Inset compares Ang II responses in Dex and control groups. Each point represents mean ± S.E.M.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
This investigation demonstrated enhanced contractility in mesenteric arteries, but not aortae, from rats with glucocorticoid-programmed hypertension. Functional changes in the mesenteric arteries were not, however, associated with an increase in the acute pressor response to Ang II in vivo. This suggests that increased Ang II-dependent vasoconstriction does not contribute to elevated blood pressure in these animals. Similarly, enhanced sensitivity to chronic blood pressure elevation in response to Ang II was probably the result of increased basal renin-angiotensin-aldosterone system (RAAS) activity rather than to changes in the resistance vasculature. We conclude that a non-selective, systemic change in vascular function and structure is unlikely to contribute to hypertension programmed by exposure to glucocorticoids in utero.

Glucocorticoid exposure, whether in rats in utero (Docherty et al. 2001) or to rat arteries in vitro (Ullian et al. 1996), can influence contraction by selective upregulation of contractile receptors in the vascular smooth muscle and/or by altering the production of endothelium-derived nitric oxide (Anwar et al. 1999, Johns et al. 2001). Impaired endothelium-dependent relaxation has been reported in arteries from rats after maternal dietary restriction (Lamireau et al. 2002, Khan et al. 2004, 2005). The present study, however, consistent with another recent report (Ozaki et al. 2001), found no impairment of endothelium-dependent relaxation in either aortae or mesenteric arteries from the Dex-treated rats. It is unlikely, therefore, that programmed endothelial cell dysfunction contributes to the elevation of blood pressure in this model.

Glucocorticoid-dependent changes in contractile function are agonist-dependent and involve several distinct mechanisms; increased -adrenergic contraction appears to be receptor-independent (Smith et al. 1987), whereas enhanced Ang II-mediated contraction is secondary to AT₁-receptor upregulation (Ullian et al. 1992). Mechanisms for other agonists are less well established (Ullian 1999). In the current study, the comparison of functional results from aortae and mesenteric arteries indicates that, as in prenatal protein restriction in rats (Torrens et al. 2003) or prenatal Dex administration in sheep (Docherty et al. 2001), functional changes in Dex-programmed hypertension vary in arteries from different anatomical locations. In the aorta, the failure of prenatal glucocorticoid exposure to enhance contractility (indeed, the tendency was for reduced contraction) suggests that there is no upregulation of contractile receptors in this vessel. Similarly, the enhanced contraction observed in mesenteric arteries from the Dex-treated rats was receptor-independent – the failure of Ang II to contract resistance arteries in isometric systems has been reported previously (Falloon et al. 1995). Given that endothelium-dependent relaxation is unaltered in these animals, the enhanced contraction in mesenteric arteries is probably due to changes in the vascular smooth muscle. Histological analysis indicated that structural remodelling was not a factor, suggesting, therefore, changes in post-receptor signal transduction. This would be consistent with persistence into adult life of glucocorticoid-mediated modulation of G-proteins (Haigh et al. 1990), second messengers (e.g. inositol triphosphate (Sato et al. 1992)) or sodium–calcium ion exchange (Smith & Smith 1994).

Acute and chronic infusions of Ang II in vivo were used to assess different mechanisms of blood pressure regulation. The use of Ang II is particularly relevant, as changes in the RAAS are implicated in programmed elevations of blood pressure: for example, AT₁-receptor antagonism in early postnatal life prevents development of hypertension after maternal dietary restriction in the rat (Sherman & Langley-Evans 1998). Acute administration of a pressor dose of the hormone assesses immediate, AT₁-receptor- mediated changes in steroidogenesis and vasoconstriction. Adrenal sensitivity to Ang II was not different, as indicated by similar elevation of aldosterone levels in both groups. Continuous infusion of Ang II below the threshold required for an immediate vasoconstrictor response is a widely used protocol for investigating long-term pressor effects, including hypertrophy and hyperplasia of smooth muscle cells in resistance arteries (Griffn et al. 1991, Su et al. 1998). Over this time course, elevated aldosterone levels are not sustained, although PRA was markedly suppressed, reflecting adrenal compensation for high Ang II levels, as is well recognised. Importantly, however, aldosterone levels were higher in Dex-treated animals at baseline and after Ang II, and PRA was not suppressed in the face of systemic hypertension. This suggests that there is increased RAAS activity in the basal state in the Dex-programmed animals, either as a result of a primary abnormality of renin secretion or perhaps secondary to sympathetic nervous system activation (Pladys et al. 2004). This is consistent with previous results with a different Dex paradigm in the rat, suggesting programming of increased RAAS activity (O’Regan et al. 2004). It is surprising, however, that Ang II-mediated suppression of PRA is increased in rats exposed to Dex in utero. The mechanism responsible for this alteration cannot be identified in the present study, although it may relate to higher blood pressure response with increased renal perfusion pressure.

The lack of effect of Dex on pressor responses to acute Ang II, consistent with the data from isolated vessels, supports the conclusion that receptor-mediated contraction is not enhanced after prenatal exposure to Dex. Chronic Ang II infusion, in contrast, produced an enhanced blood pressure elevation in the Dex group, indicating a greater sensitivity to Ang II. This could not be attributed to vascular remodelling, as the medial area was unchanged in resistance arteries. It is possible that the increased sensitivity to chronic Ang II is due to glucocorticoid-mediated sensitisation of contractile signal transduction (Hai et al. 2002) and/or free radical formation and inhibition of endothelium-derived nitric oxide (Rajagopalan et al. 1996), mediated in part by AT₁- receptors (McEwan et al. 1998). Alternatively, since there is evidence of activation of the RAAS programmed by glucocorticoids, there may be increased sodium retention during chronic Ang II infusion. These mechanisms will require further studies, but the combination of lack of enhanced acute pressor response to Ang II and lack of vascular remodelling during chronic Ang II infusion does not suggest that altered structure or function of resistance vessels underlies glucocorticoid-programmed hypertension.

	Funding

 
This work was supported by grants from the British Heart Foundation (P W F H and B R W), Wellcome Trust (J R S) and Medical Research Council (C J K).

	Acknowledgements

 
We thank Dr J J Morton for providing reagents for plasma renin assays and Sharon Rossiter for blood pressure measurements. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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Received 7 November 2005
Accepted 9 December 2005
Made available online as an Accepted Preprint 12 December 2005

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