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Biology of Reproduction 67, 1430-1434 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Effects of Pregnancy and Female Sex Steroid Hormones on Calcitonin Gene-Related Peptide Content of Mesenteric Artery in Rats1

P. Lanluaa,b, R.D. Bukoskic,d, S.J. Wimalawansac, and C. Yallampalli2,a,b

a Departments of Obstetrics and Gynecology, b Anatomy and Neurosciences, c Internal Medicine, The University of Texas Medical Branch, Galveston, Texas 77555 d Cardiovascular Disease Research Program, Julius L. Chamber's Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina 27707


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Calcitonin gene-related peptide (CGRP) levels in plasma and the dorsal root ganglia (DRG) are increased during pregnancy and in ovariectomized rats injected with ovarian hormones. Vasodilatory responses to CGRP are also increased in these animals. In the present study, we hypothesized that pregnancy and ovarian hormones elevate the contents of CGRP in perivascular nerves. We assessed CGRP-dependent mesenteric vascular relaxation induced by electrical field stimulation (EFS) and arterial content of CGRP. Because the mesenteric artery represents resistance vessels, segments of mesenteric arteries collected from female rats at different stages of the estrous cycle, pregnancy, or postpartum and from male rats were used in this study. The EFS-induced relaxation in the presence and absence of CGRP8–37, an antagonist of CGRP, was used to measure CGRP-dependent relaxation, and radioimmunoassay (RIA) of tissue homogenates was used to assess changes in CGRP content in mesenteric branch arteries. The results show that CGRP-dependent, EFS-induced relaxation response was lower in female rats at diestrus and proestrus than in male rats, and no statistically significant differences were observed between Gestational Day 20 and Postpartum Day 2. The RIA revealed significantly lower mesenteric artery CGRP levels in female rats at proestrus, gestation, and postpartum than in female rats at diestrus or in male rats. We conclude that no correlation exists between CGRP-dependent, EFS-induced relaxation and CGRP content in the mesenteric arteries of these animal groups. Because both CGRP levels in DRG and serum are reported to be elevated, the reduced CGRP content in the vasculature during pregnancy and proestrus implicate enhanced basal release of CGRP at the nerve terminal in these animals.

ovulatory cycle, pregnancy, steroid hormones


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Calcitonin gene-related peptide (CGRP) is a potent vasodilator that decreases blood pressure via peripheral vasodilation [1, 2]. The primary sites of CGRP synthesis are the sensory neurons of the dorsal root ganglia (DRG) [3, 4] that send processes centrally to the spinal cord and peripherally to various tissues, including blood vessels [5]. The CGRP synthesized in DRG is transported through axons to the nerve terminals in perivascular tissues. After its release from perivascular sensory nerve terminals, CGRP has been suggested to bind to two types of receptors: CGRP-R1 and CGRP-R2. These receptors are distinguished by their affinities to hCGRP8–37 and the linear analogue to CGRP, [Cys(ACM)2,7]hCGRP. The CGRP-R1 is blocked efficiently by CGRP8–37, whereas [Cys(AMC)2,7]hCGRP is a potent agonist for CGRP-R2 [4, 6, 7]. However, recent reports cast doubt on the existence of CGRP-R2 and suggest possible variations in receptor affinities for CGRP8–37 in functional studies based on various tissue-dependent factors [8]. The perivascular nerves on mesenteric branch arteries contain comparatively more CGRP than those on the vein [9–13], and CGRP receptors are expressed on the smooth muscle cells of the mesenteric artery [13–19]. The CGRP has pronounced dilator effects on mesenteric arteries, and these vessels contribute to the regulation of gastrointestinal vascular resistance and regional blood flow [12].

In pregnant rats, the vasodilatory responses to exogenous CGRP are significantly elevated, indicating increased vasodilatory sensitivity to CGRP during pregnancy [20]. This increased vasodilation after CGRP administration during pregnancy appears to result from decreased total vascular resistance, particularly to coronary, mesenteric, and renal vascular beds [21]. Both estradiol and progesterone treatment of ovariectomized (ovx) rats caused increased vasodilatory responses to CGRP [20, 21]. Additional roles for CGRP in the regulation of vasodilation during pregnancy were demonstrated by the elevated blood pressure on continuous infusion of the CGRP-receptor antagonist CGRP8–37. In addition, mean arterial blood pressure increases in CGRP-deficient mice were significantly greater in males than in females [22]. However, if the levels of CGRP at perivascular sensory nerve endings are also altered during pregnancy and by female sex steroid hormones is unclear. The mechanisms underlying the storage and release of CGRP at the perivascular nerve terminals are not fully understood.

Plasma CGRP levels are elevated during pregnancy in both humans [23, 24] and rats [25]. Both estradiol and progesterone were also shown to elevate serum CGRP levels in ovx rats [25]. In addition, the plasma CGRP levels were 1) higher in women taking contraceptive pills than in women not taking contraceptives and in men [26] and 2) higher in postmenopausal women taking hormone-replacement therapy (HRT) than in women not taking HRT [27].

Thus, CGRP levels in the circulation are higher when levels of female steroid hormones are elevated. In addition, our previously published [28, 29] studies have shown that CGRP synthesis in DRG is upregulated in ovx rats with ovarian steroid hormone injection and in pregnant rats. The female sex steroid hormones estradiol and progesterone, in addition to increasing CGRP synthesis in DRG, may also facilitate the transport and release of CGRP at the perivascular nerves to increase CGRP levels in plasma. Therefore, we hypothesized that elevated female sex steroid hormone levels during pregnancy and proestrus/estrus would increase CGRP release at the mesenteric arterial perivascular nerves and, therefore, decrease vascular resistance. We tested the hypothesis by assessing CGRP-dependent mesenteric vascular relaxation induced by electrical field stimulation (EFS) and arterial content of CGRP by using radioimmunoassay (RIA). We chose the mesenteric artery because true resistance arteries, including those in the mesenteric circulation, regulate gastrointestinal vascular resistance and regional blood flow and contribute to regulation of blood pressure [12]


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

All procedures were approved by the Animal Care and Use Committee at the University of Texas Medical Branch and were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. We purchased adult male, adult female nonpregnant (8–9 wk old), and pregnant (Gestational Day 14) Sprague-Dawley rats (Harlan Sprague-Dawley, Houston, TX). All rats were maintained in the colony room with a fixed 12L:12D photoperiod and free access to water and food.

The female rats at different gestational days or at various stages of the estrous cycle were used in the present study. The pregnant rats were killed at Gestational Day 18, 20, or 22 or at Postpartum Day 2; all fetuses and pups were killed by halothane inhalation. The stage of estrous cycle in the nonpregnant rats was assessed by microscopically identifying the types of cells present in a vaginal flush [30]; these rats were grouped as diestrus, proestrus, or estrus and then killed. The arteries from male rats were used as a control for these groups.

Isometric Force Wire Myograph

The tissue-preparation procedure for the isometric force wire myograph is similar to that described by Wang and Bukoski [31], with slight modifications. All rats were killed by exsanguination under deep anesthesia induced by i.p. injection of ketamine (50 mg/kg) and xylazine (8 mg/kg). The small intestine, with the blood supply intact, was excised and immersed in a physiological salt solution (PSS) on ice containing (in mmol/L): NaCl (114), KCl (4.7), KH2PO4 (1.15), Na2HPO4 (1.10), MgSO4·7H2O (1.18), NaHCO3 (15), CaCl2 (1.50), and glucose (5.0). The secondary branches of the mesenteric artery with intact endothelium were separated from veins and connective tissue and then cut into 2-mm lengths. Two tungsten wires (diameter, 28 µm; Whitmor Wirenetics, Valencia, CA) were inserted through the lumen of each arterial segment. Next, the arterial segments were mounted onto Teflon blocks of a wire myograph (Kent Scientific Corporation, Litchfield, CT), and the Teflon blocks were connected by platinum wires to an SD9J stimulator (Grass Instrument Co., Warwick, RI) to generate EFS. The segment was incubated in a chamber of PSS gassed with 95% air/5% CO2 to maintain pH 7.4 at 37°C for 15 min. The arterial segment with an unstretched diameter of 125–150 µm was then stretched to a length that yielded a diameter of 200–225 µm and allowed to equilibrate for another 15 min. The segment was induced to contract by the addition of norepinephrine (NE) until reproducible responses were obtained. A concentration-response curve was generated by the cumulative addition of NE from 30 nmol/L to 100 µmol/L, following which the dose of NE that induced 70% of the maximal contractile response (ED70) was estimated. The NE dose at ED70 was then added three to four times until reproducible contractile responses were observed.

To assess EFS-induced relaxation, 10 µmol/L of guanethidine monosulfate was added to the chamber for 15 min to block catecholamine release from the sympathetic nerves, following which either CGRP8–37 (an antagonist of CGRP-R1) or 5 µl of dH2O (as control) were added into the myograph chamber. Several concentrations of CGRP8–37 (1, 3, and 10 µmol/L) were tested during initial experiments to identify a suitable dose of CGRP8–37 for blockade of CGRP-dependent relaxation responses. Because pretreatment with 10 µmol/L of CGRP8–37 did not increase the level of relaxation reduction over and above that observed with 3 µmol/L of CGRP8–37, the latter concentration was used in subsequent experiments. The arterial segments were precontracted with 5 µmol/L of phenylephrine HCl, a pure {alpha}-agonist, and electrically stimulated with a Grass SD9J stimulator for a 10-sec period using the following parameters: voltage = 70 V, frequency = 10 pulses per second, and duration = 2 msec. For each segment, EFS-induced relaxation was calculated as a percentage of precontracted tension induced by phenylephrine (100%).

RIA for CGRP

The CGRP content in isolated mesenteric branch arteries was determined using a CGRP-RIA kit (Phoenix Pharmaceuticals, Inc., Belmont, CA). The mesenteric arteries were homogenized with RIA buffer, and the homogenates were centrifuged at 5000 x g at 4°C for 10 min. The supernatant in each sample was separated and used for RIA reactions in duplicate, following the manufacturer's instructions. The CGRP content was expressed as pg/mg total protein in the supernatant, which was measured by a BCA kit (Pierce, Rockford, IL).

Statistical Analysis

The number of animals in each group varied from 5 to 10. Results are presented as the mean ± SEM. The statistical differences between means of the experimental groups and the control group were compared by ANOVA followed by the Bonferroni test. A P value < 0.05 was considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Initial studies assessed the EFS-induced vasodilator responses of arteries taken from intact male and female rats at various stages of the estrous cycle: diestrus, proestrus, and estrus. Data from female rats are presented as a single group as well as for various stages of the estrous cycle (Fig. 1). The maximal relaxation observed in response to EFS in the absence of CGRP8–37 was similar in vessels isolated from each group (Fig. 1); no significant differences were observed between males and females either as a group or at each stage of the estrous cycle. However, differences were observed in the CGRP-sensitive component of EFS-induced relaxation measured in the presence of CGRP8–37. Pretreatment with CGRP8–37 had no effect on the EFS-induced relaxation responses of intact females as a group (9.5 ± 3.5%, n = 16) or of females at diestrus or proestrus, but it significantly attenuated the relaxation responses of arteries of females in estrus and intact males (females in estrus were reduced by 24.52 ± 6.08% [n = 5, P < 0.05], whereas males were attenuated by 42.93 ± 4.1% [n = 5, P < 0.001]).



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  		FIG. 1. Effect of CGRP8–37 (CGRP-receptor antagonist) on EFS-induced relaxation of mesenteric arteries of male rats (M, n = 5), female rats as a group (F, n = 16), or at individual diestrus (D, n = 6), proestrus (P, n = 5), and estrus (E, n = 5). The arterial segments of each animal were incubated in the absence or presence of CGRP8–37 before EFS. Data are presented as the percentage of EFS-induced relaxation without (striped bars) and with (filled bars) CGRP8–37. Asterisks indicate P < 0.05 (*) and < 0.001 (***) compared within each group between the absence or presence of CGRP8–37 (ANOVA)

To learn whether the differences in the CGRP-dependent component of relaxation in these animals was linked with CGRP content in the mesenteric vasculature, we assessed the CGRP content in tissue homogenates as described in Materials and Methods. The CGRP peptide was present in mesenteric branch arteries of each of the animal groups studied: intact males and females in diestrus, estrus, and proestrus. Moreover, the CGRP content was greatly reduced in the proestrous females, during which time estrogen levels are reported to be greatly elevated compared with the other groups (Fig. 2).



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  		FIG. 2. CGRP contents in the mesenteric arteries of male (M) rats and female rats at diestrus (D), proestrus (P) and estrus (E). Arterial segments were collected and processed for RIA of CGRP. Data are presented as pg CGRP/mg total protein in the homogenate (mean ± SEM, n = 8). The different letters (a, b) indicate significant difference at P < 0.001 (ANOVA).

We next assessed the pregnancy-related changes in EFS-induced relaxation and mesenteric branch artery CGRP contents. The CGRP-dependent, EFS-induced relaxation of vessels isolated from nonpregnant rats at diestrus or from rats at Gestational Day 20 and Postpartum Day 2 is presented in Figure 3. The EFS induced a significant degree of relaxation in each of the groups examined. However, pretreatment with the CGRP antagonist was without effect. To provide information about possible correlations between the lack of CGRP-dependent, EFS-induced relaxation and vessel wall CGRP content, we assessed the level of CGRP in homogenates of arteries isolated from rats at Gestational Days 18, 20, and 22 and Postpartum Day 2 and then compared them with nonpregnant rats in diestrus. Compared with rats in diestrus, a marked decrease in CGRP content was observed in the vessels isolated from animals at each day of pregnancy as well as at Postpartum Day 2 (Fig. 4).



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  		FIG. 3. Effect of CGRP8–37 on EFS-induced relaxation of mesenteric arteries from female rats at diestrus (D), Gestational Day 20 (D20), and Postpartum Day 2 (PP2). The arterial segments of each animal were incubated in the presence and absence of CGRP8–37 before EFS was performed. Data are presented as the percentage of EFS-induced relaxation with (filled bars) and without (striped bars) CGRP8–37 (ANOVA, n = 6)



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  		FIG. 4. CGRP levels in the mesenteric arteries of female rats at diestrus (D), Gestational Day 18 (D18), Gestational Day 20 (D20), Gestational Day 22 (D22), and Postpartum Day 2 (PP2). Arterial segments were collected and processed for CGRP-RIA. Data are presented as pg CGRP/mg total protein (mean ± SEM, n = 5 except for D [n = 8]). Asterisks indicate P < 0.01 (**) and < 0.001 (***; ANOVA)


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have previously reported that both pregnancy and female sex steroid hormones stimulate CGRP synthesis in DRG, increase circulating levels of CGRP, enhance the vasodilatory responses to CGRP, and decrease peripheral vascular resistance. The present study was performed to test the hypothesis that in vivo variations of ovarian hormones modulate CGRP-dependent, perivascular sensory nerve-mediated relaxation of subsequently isolated mesenteric branch arteries. One major finding of the present study was that EFS-induced, sensory nerve-dependent relaxation of the isolated mesenteric branch arteries is remarkably consistent across the various experimental groups that were studied, even though the CGRP-dependent component was quite variable. The second finding is that although ovarian hormones modulate arterial wall CGRP content, this does not predict the degree of CGRP-dependent vasorelaxation. These findings, together with those of our previous reports [20, 21, 25, 28, 29], suggest that pregnancy and steroid hormones modulate not only CGRP-induced vasodilatory functions but also CGRP synthesis in DRG and release at perivascular nerves.

Normal plasma CGRP levels are reported to be higher in women than in men, and they are reported to be highest of all in women taking contraceptive pills containing 50 µg of ethinyl estradiol and 100 µg of Levonorgestrel [26]. The CGRP concentrations in the plasma also reportedly increase during pregnancy and decrease postpartum in humans [23, 24] and rats [25]. In addition, female hormone treatments are known to elevate CGRP levels in the serum of both ovx rats and postmenopausal women [25, 27]. Therefore, plasma CGRP levels are increased when the levels of the female hormones, 17ß-estradiol and progesterone, are elevated. Our own previous studies have shown elevated CGRP (mRNA and proteins) levels in DRG and serum during pregnancy [23–25, 28]. Taken together, these data support the idea of an increase in basal release of CGRP from peripheral nerve processes in these animals.

The primary sites of CGRP synthesis are the sensory neurons of the DRG [3, 4]. Our previous studies [28, 29] have demonstrated that CGRP levels in the DRG are increased in ovx rats injected with ovarian steroid hormones and in pregnant rats. Because CGRP levels are decreased in the DRG of ovx rats without female hormone injections and in postpartum rats, a direct correlation appears to exist between the high levels of these ovarian hormones and CGRP synthesis in the DRG. On the whole, CGRP levels in plasma and the DRG appear to be increased when the female steroid hormones are elevated.

The mechanisms of CGRP transport and release are not fully understood. The CGRP is primarily synthesized in sensory neurons of the DRG [3, 4] that send the peripheral processes to various organs, including the blood vessels [5]. Because both synthesis of CGRP in DRG and levels of CGRP in the serum are elevated, we postulated that CGRP transport and release could also be increased in females at proestrus and during pregnancy.

We therefore reasoned that the magnitude of CGRP-dependent relaxation by EFS-induced activation of perivascular sensory nerves might be enhanced in states with elevated serum CGRP. In contrast to this prediction, we found a large degree of variability in the magnitude of CGRP-mediated relaxation in arteries isolated from the various treatment groups. For example, CGRP-dependent relaxation was observed in arteries of male rats and intact female rats in estrus, but not in female rats in diestrus or proestrus (Fig. 1). However, EFS-induced relaxation was identical and independent of CGRP in rats at diestrus as well as at Gestational Day 20 and Postpartum Day 2 (Fig. 3).

These data are interesting for several reasons. First, arteries isolated from animals with very different hormone profiles appear to have maximal relaxation responses very similar to that of perivascular sensory nerve EFS. This suggests that a variety of processes are acting to maintain the vasodilator capacity of the nerve network. An implication of this observation is that redundant pathways maintain a constant vasodilator capacity. This could be the result of preferred release of other vasodilator transmitters, such as nitric oxide (NO) [32] or the endocannabinoids [33], or the result of changes in postjunctional processes.

Another prediction we made was that a correlation would be found between the degree of CGRP-dependent relaxation and the CGRP content of the isolated vessel segments. From the general pattern that was observed, however, absolutely no correlation between CGRP content and CGRP-dependent, EFS-induced relaxation was found. A very good example can be seen by a comparison of the data in Figures 3 and 4, in which the arteries of rats at diestrus have nearly twice as much CGRP as those at Gestational Day 20 and Postpartum Day 2, yet none of the groups exhibit CGRP-dependent, EFS-induced relaxation.

Several factors influence the release of CGRP in the nerves. The release of CGRP from DRG neurons in culture has been shown to be regulated by nerve growth factor (NGF) [34, 35], bradykinin [36], and prostaglandins [37]. Moreover, CGRP release from the perivascular nerves of the mesenteric artery is induced by NO and inhibited by an NO synthase inhibitor [38]. In addition, NGF, bradykinin, prostaglandins, and NO may regulate CGRP release from the perivascular nerves. All these agents also are induced during the stages of elevated ovarian steroid hormones, as occur during gestation. Our recent report has demonstrated that NGF levels in DRG are increased in pregnant rats at Gestational Day 18 [29]. Furthermore, plasma levels of bradykinin have been reported to be significantly upregulated in postmenopausal women receiving HRT [39]. Prostaglandins in the serum have also been reported to be upregulated in pregnant women when compared with those in nonpregnant women [40–42]. In addition, the enzymes involved in NO synthesis are increased in several tissues during pregnancy [43, 44]. Considering all this information, it seems clear that multiple sites of regulation exist and that many of these could be sites where ovarian hormones, either alone or in combination, could have significant actions.

Previous reports strongly suggest a role for the CGRP system in regulation of vascular adaptations that occur during pregnancy and with steroid hormones [20, 21]. Synthesis of CGRP in DRG [28; 29] and circulating levels of CGRP [25] are elevated during pregnancy and on steroid hormone injection to ovx rats. In addition, vasodilatory responses to CGRP in normotensive or hypertensive rats are enhanced during pregnancy and with steroid hormones [20, 45, 46]. The present study suggests that pregnancy and, perhaps, elevated steroid hormones could accelerate the release of CGRP from perivascular nerves. Further studies are required to fully elucidate the mechanisms involved in CGRP release at nerve terminals.

In summary, we have tested the hypothesis that in vivo ovarian hormone status of rats modulates the CGRP-dependent, perivascular sensory nerve-mediated relaxation of subsequently isolated arteries in a manner that is linked with CGRP content of the arterial wall. The results indicate that whereas variation of ovarian hormones can, in some instances, alter the arterial wall CGRP content and modulate the relaxation responses of subsequently isolated arteries, the stated hypothesis is an oversimplification. A highly complex series of interactions appear to be present among the ovarian hormones, CGRP production and release by the sensory nerve processes, and the vasodilator responsiveness of the vascular effect organ.


   ACKNOWLEDGMENTS
 
We would like to thank Ms. K.S. Mitchell for typing, Ms. P. Necessary for editorial comments, and Mr. J. Helms for graphic assistance.


   FOOTNOTES
 
1 Supported by the following National Heart Blood and Lung Institute Grants: HL-58144 (C.Y.), HL59868 (R.D.B.), and HL 64761 (R.D.B.). Back

2 Correspondence: Chandrasekhar Yallampalli, Department of Obstetrics and Gynecology, The University of Texas Medical Branch, 301 University Boulevard, Route 1062, Galveston, TX 77555-1062. FAX: 409 747 0475; chyallam{at}utmb.edu Back

Received: 22 April 2002.

First decision: 21 May 2002.

Accepted: 5 June 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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