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Endocrinology, doi:10.1210/en.2006-0567
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Endocrinology Vol. 147, No. 11 5126-5131
Copyright © 2006 by The Endocrine Society

Relaxin Is Essential for Systemic Vasodilation and Increased Global Arterial Compliance during Early Pregnancy in Conscious Rats

Dan O. Debrah, Jackie Novak, Julianna E. Matthews, Rolando J. Ramirez, Sanjeev G. Shroff and Kirk P. Conrad

Bioengineering (D.O.D., S.G.S.), University of Pittsburgh; Obstetrics, Gynecology, and Reproductive Services (J.N., J.E.M., R.J.R., K.P.C.), University of Pittsburgh School of Medicine and Magee-Women’s Research Institute; and Cell Biology and Physiology (K.P.C.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Kirk P. Conrad, M.D., Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 Southwest Archer Road, M552, P.O. Box 100274, Gainesville, Florida 32610-0274. E-mail: kpconrad{at}ufl.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
During early pregnancy, there are marked increases in cardiac output (CO) and global arterial compliance (AC), as well as decreases in systemic vascular resistance (SVR). We recently reported that administration of recombinant human relaxin to nonpregnant female rats elicits changes in systemic hemodynamics and arterial mechanical properties similar to those observed during normal pregnancy. In the present study, we directly tested whether endogenous relaxin mediates the cardiovascular adaptations of pregnancy by neutralizing circulating relaxin with monoclonal antibodies during early gestation. Relaxin neutralizing antibodies were administered daily, beginning on d 8 of rat gestation, to block the functional effects of circulating relaxin. Systemic hemodynamics and arterial properties were assessed between gestational d 11 and 15 using techniques we have previously reported. Pregnant rats administered the neutralizing antibodies failed to exhibit the gestational increases in stroke volume, CO, and global AC or decreases in SVR that were observed in control pregnant rats administered an irrelevant antibody against fluorescein or PBS. In fact, in the pregnant rats administered the relaxin neutralizing antibodies, cardiovascular parameters were not statistically different from those in virgin rats. Interestingly, small renal and first-order mesenteric arteries isolated from midterm pregnant rats administered either relaxin-neutralizing or control antibodies did not exhibit any changes in passive mechanical properties compared with virgin rats. These findings indicate that circulating relaxin mediates the transition of the systemic circulation from the virgin to the pregnant state in the gravid rat model, suggesting a potential role for aberrant relaxin regulation in abnormal pregnancies wherein these cardiovascular adaptations are inadequate or excessive.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE CARDIOVASCULAR SYSTEM during pregnancy is characterized by several adaptations in systemic hemodynamics and arterial mechanical properties that ultimately contribute to the adequate uteroplacental perfusion required for proper fetal development without compromising maternal function (1). These changes include a marked increase in cardiac output (CO), a modest decrease in mean arterial pressure (MAP), and a profound reduction in both the steady and pulsatile components of arterial load as quantified by a reduction in systemic vascular resistance (SVR) and an increase in global arterial compliance (AC), respectively. These alterations are observed early during pregnancy, typically peak at the end of the first or beginning of the second trimester in women, and persist thereafter.

The pregnancy factor(s) that mediate this vasodilatory response is not completely understood. Historically, it has been suggested that the sex steroids are responsible for these changes in cardiovascular function during pregnancy (1, 2, 3, 4). However, we have hypothesized that the ovarian hormone relaxin is involved. Relaxin is a peptide hormone of the insulin/relaxin family of peptides that is secreted by the corpus luteum during pregnancy in mice, rats, and humans (5). Serum levels of relaxin in rats increase in pregnancy concurrent with the changes in cardiovascular function (4, 5, 6). Furthermore, we previously showed that relaxin is essential for the maternal adaptations that occur in the renal circulation during pregnancy. That is, elimination or neutralization of circulating relaxin in gravid rats abrogates the increase in renal plasma flow and glomerular filtration and also prevents the reduction in myogenic reactivity of small renal arteries that is observed during pregnancy (7). Also, administration of porcine or recombinant human relaxin (rhRLX) to nonpregnant rats elicits renal vasodilatory responses similar to those observed during early pregnancy (8).

In addition to its effects on the renal circulation, we have shown that exogenous administration of rhRLX to nonpregnant rats elicits changes in systemic arterial properties similar to those observed during pregnancy: reduced SVR and increased global AC (9). Interestingly, the vasodilatory properties of relaxin are independent of gender (10, 11). The primary goal of the present study was to determine whether endogenous, circulating relaxin mediates the changes in cardiovascular function during midterm rat pregnancy. Specifically, we set out to test whether neutralizing circulating relaxin with antibodies would prevent the normal gestational changes in systemic hemodynamics and arterial properties. Of note, our previous work demonstrated that one of the possible mechanisms through which relaxin elicits an increase in global AC is by altering the passive mechanical properties of arteries (9). Accordingly, another goal of the present study was to investigate whether neutralization of circulating relaxin would prevent any changes in the passive mechanical properties of small renal and larger mesenteric arteries isolated from midterm pregnant rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Long-Evans female rats (age 12–14 wk) were purchased from Harlan Sprague Dawley (Frederick, MD) or Taconic (Germantown, NY). They were provided PROLAB RMH 2000 diet containing 0.48% sodium (PME Feeds Inc., St. Louis) and water ad libitum, and were maintained on a 12-h light, 12-h dark cycle. This investigation conformed with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85-23, revised 1996). After being habituated to the experimental conditions, rats were either housed with males or remained as virgin controls. The presence of spermatozoa in the vaginal lavage was considered d 0 of gestation.

Chronic instrumentation
The surgical procedures were previously described in detail (9). Briefly, virgin controls and pregnant rats (gestational d 4–6) were instrumented using sterile technique with: 1) a tygon catheter (0.015-in. ID, 0.030-in. OD) implanted in the right jugular vein with the tip located at the junction of the anterior vena cava and right atrium; 2) a thermodilution microprobe (22 cm long, 1.5 Fr; Columbus Instruments, Columbus, OH) implanted in the abdominal aorta via the left femoral artery with the tip advanced to 1.0 cm below the left renal artery; 3) a mouse pressure catheter (TA11PA-C20/C10, 1.2 Fr; Data Science International, St. Paul, MN) introduced via the right carotid artery with the tip lying at the junction of the right carotid artery and aortic arch; and 4) a tygon catheter implanted in the inferior vena cava via the left femoral vein.

Administration of relaxin-neutralizing antibodies
Neutralizing antibodies against rat relaxin (MCA1; n = 7 pregnant rats) or control antibodies against fluorescein (MCAF; n = 8 pregnant rats) were administered via daily iv injection between 1200 and 1600 h for up to 8 d beginning on d 8 of gestation. Each injection containing 5.0 mg of antibody in 0.5 ml of PBS was infused over 5 min into the femoral venous catheter (7, 12, 13). Other pregnant rats were administered PBS vehicle (n = 6) to serve as a second untreated-pregnant control group. Additionally, seven virgin rats were instrumented as described above and systemic hemodynamics and arterial mechanical properties were assessed using the techniques described below.

Systemic hemodynamics and arterial mechanical properties
Systemic hemodynamics and arterial mechanical properties were assessed on two separate days between gestational d 11 and 15 using techniques we have previously described (9). The average values of each given variable assessed on the two separate days from each animal was taken to be the representative value of that variable for that animal. Each measurement consisted of six to 10 recordings of CO and blood pressure waveforms obtained when the rat was either sleeping or in a resting state. At least 5–10 min were allowed between recordings and they were obtained between 0900 and 1500 h. Arterial mechanical properties were quantified in terms of SVR and global AC. Systemic vascular resistance was calculated as the ratio of MAP to CO. We calculated global AC using two independent indices, the ratio of stroke volume (SV) to pulse pressure (PP), and ACarea, which was obtained by analyzing the diastolic decay of the aortic pressure waveform (9).

Postmortem procedures
On the last day of experimentation (gestational d 14 or 15), rats were anesthetized with 60 mg/kg iv pentobarbital. Blood was obtained from the abdominal aorta for measurement of serum progesterone concentrations (7) and serum osmolality (Vapor Pressure Osmometer; Wescor Inc., Logan, UT). The placement of each implanted catheter was verified. The left kidney and mesenteric arcade were removed for isolation of small renal arteries and larger mesenteric arteries and subsequent assessment of passive mechanical properties. The uterus was removed and the numbers of viable fetuses and reabsorptions and individual fetal and placental wet weights were recorded. Finally, the cervix was carefully dissected from the vagina and the wet weight measured.

In vitro arterial passive mechanics.
The kidney and mesenteric arcade were placed in ice-cold HEPES buffered physiological saline solution (a modified Kreb’s buffer) composed of (in mmol/liter): sodium chloride 142, potassium chloride 4.7, magnesium sulfate 1.17, calcium chloride 2.5, potassium phosphate 1.18, HEPES 10, glucose 5.5 (pH 7.4 at 37 C). A stereo dissecting microscope, fine forceps, and iridectomy scissors were used to isolate renal interlobar (unpressurized ID 100–200 µm) and first-order mesenteric (unpressurized ID 200–300 µm) arteries. Each arterial segment was then transferred to an isobaric arteriograph (Living Systems Instrumentation, Burlington, VT) and mounted on two glass micro-cannulae suspended in the chamber. After the residual blood was flushed from the lumen of the artery, the distal cannula was occluded to prevent flow. The proximal cannula was attached to a pressure transducer, a pressure servo-controller and a peristaltic pump that maintained a selected intraluminal pressure that was changed in a stepwise manner. An electronic dimension analyzing system was used to measure arterial internal and external diameters.

The vessels were incubated in the bath with 10–4 M papaverine and 10–2 M EGTA in calcium-free HEPES physiologic saline solution. After a 30-min equilibration period, transmural pressure was increased in 13 steps beginning at 0 mmHg up to 120 mmHg. Inner and outer diameters as well as wall thickness were measured after each pressure step when the vessel had reached a steady state. Midwall radius (Rm) and circumferential wall stress ({sigma}) were calculated from these data as previously described (9, 14). Stress ({sigma})-strain ({epsilon}) relationships for each isolated vessel were also computed from the Rm data. Strain was calculated as follows: (Rm – Rmo)/Rmo; where Rmo represents the midwall radius at transmural pressure 0 mmHg.

Statistical analysis
Data are presented as mean ± SEM. One-factor randomized block ANOVA was used with three levels corresponding to the MCA1 and MCAF-treated pregnant rats, and the virgin controls. If a significant main effect was observed, then comparisons among groups were performed using Fisher’s least significant difference (LSD) test. The Mann-Whitney-U test was used to compare mean values of pup and placental wet weights, serum progesterone concentrations, as well as the number of viable and reabsorbed pups between the MCA1 and MCAF antibody treatment groups. Least squares regression analysis was performed on {sigma}-Rm and {sigma}-{epsilon} relationships. Analysis of excess variance (or extra sum of squares) (15) was used to compare these relationships between the two pregnant and virgin groups. P < 0.05 was taken to be significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of relaxin-neutralizing antibodies on systemic hemodynamics
Systemic hemodynamic variables for pregnant and virgin rats are illustrated in Fig. 1Go. There was no statistically significant difference in HR or MAP among the virgin and MCA1 and MCAF antibody-treated pregnant groups (Fig. 1Go, A and B). Stroke volume (Fig. 1CGo) and CO (Fig. 1DGo) were both significantly increased in midterm pregnant rats administered the irrelevant MCAF antibody against fluorescein compared with virgin controls (both P < 0.05). Importantly, the SV (0.38 ± 0.02 ml) and CO (165 ± 5 ml/min) of the pregnant rats administered the PBS vehicle instead of antibodies were comparable to the values observed in the MCAF antibody-treated gravid rats (both P = NS). In contrast, both SV and CO were significantly decreased in midterm pregnant rats treated with rat relaxin neutralizing antibodies compared with the gravid animals administered MCAF antibody (both P < 0.05) and comparable to virgin levels (both P = NS).


Figure 1
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  		FIG. 1. Systemic hemodynamics in pregnant rats administered relaxin-neutralizing antibody (MCA1) or control antibody (MCAF), and virgin rats. Pregnant rats were administered daily injections of antibodies beginning on gestational d 8. A, HR; B, MAP; C, SV; and D, CO. *, P < 0.05 vs. MCA1 (post hoc Fisher’s LSD). {dagger}, P < 0.05 vs. Virgin (post hoc Fisher’s LSD).

 
Effects of relaxin-neutralizing antibodies on systemic arterial properties
Systemic arterial properties for pregnant and virgin rats are illustrated in Fig. 2Go. Systemic vascular resistance in the MCAF-treated pregnant rats was significantly lower compared with the virgin controls. Treatment with relaxin-neutralizing antibodies completely eliminated this pregnancy-associated reduction in SVR (Fig. 2AGo). Global AC as measured by ACarea and SV/PP was significantly increased in the MCAF-treated pregnant rats compared with the virgin control group. The treatment with relaxin neutralizing antibodies completely abolished this pregnancy-associated increase in global AC (Fig. 2Go, B and C). Systemic vascular resistance and global AC for the MCAF-treated rats were similar to levels observed in the control pregnant rats administered PBS (SVR: 39.4 ± 1.7 mmHg·s/ml; ACarea: 9.7 ± 0.5 ml/mmHg; SV/PP: 11.6 ± 0.7 µl/mmHg; all P = NS).


Figure 2
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  		FIG. 2. Systemic arterial properties in pregnant rats administered relaxin-neutralizing antibody (MCA1) or control antibody (MCAF), and virgin rats. Pregnant rats were administered daily injections of antibodies beginning on gestational d 8. A, SVR; B, ACarea; and C, SV/PP. *, P < 0.05 vs. MCA1 (post hoc Fisher’s LSD). {dagger}, P < 0.05 vs. Virgin (post hoc Fisher’s LSD).

 
Effects of relaxin-neutralizing antibodies on arterial passive mechanical properties
To determine whether these relaxin-mediated changes in global AC were attributable in part to alterations in arterial passive mechanical properties, we assessed Rm-{sigma} and {sigma}-{epsilon} relationships of isolated renal and mesenteric arteries. Contrary to our expectations, pregnant rats administered the control antibody (MCAF) did not exhibit any significant changes in Rm-{sigma} (Fig. 3Go, A and B) and {sigma}-{epsilon} (Fig. 3Go, C and D) relationships compared with virgin controls. Furthermore, these relationships were not altered by administration of relaxin neutralizing antibodies (MCA1) to pregnant rats (Fig. 3Go).


Figure 3
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  		FIG. 3. Circumferential wall stress ({sigma})-midwall radius (Rm) and {sigma}-strain ({epsilon}) relationships for small renal (A and C) and mesenteric (B and D) arteries isolated from MCA1 or MCAF-treated pregnant rats and virgin controls. Original data from each animal were first fitted to a third order polynomial, which was then used to obtain interpolated data (i.e. {sigma} values for a given Rm or {epsilon}). Interpolated {sigma} data at a common value of Rm or {epsilon} were averaged over all animals within a group to yield the relationships shown here. There were no significant differences.

 
Consistent with our earlier work, the MCA1 antibody attenuated the gestational decrease of serum osmolality and increase of cervical wet weight (7). These findings confirm the efficacy of the relaxin neutralizing antibodies in vivo. There were no significant differences in fetal or placental variables between the two antibody treatment groups (Table 1Go). Nor were there any significant differences in serum progesterone concentrations between the two groups (MCA1 as previously reported (7). 119.5 ± 16.2 pg/ml; MCAF: 149.9 ± 26.0 pg/ml) as previously reported (7).


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  		TABLE 1. Fetal and placental outcomes, as well as a maternal serum osmolality and cervical wet weight

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Administration of relaxin to nonpregnant female rats elicits alterations in systemic hemodynamics and arterial mechanical properties comparable to those observed during pregnancy; male rats respond in a similar manner (4, 6, 9, 10, 16, 17). The major goal of the present study was to determine whether the endogenous, circulating relaxin of pregnancy mediates the gestational changes in the cardiovascular system. By neutralizing circulating relaxin with antibodies, we were able to show that relaxin mediates the increase in cardiac output and global arterial compliance, as well as the decrease in systemic vascular resistance during midterm pregnancy in conscious rats.

Our current findings are consistent with earlier work that showed that either neutralization of circulating relaxin by antibodies or elimination by ovariectomy, abrogated renal and osmoregulatory adaptations in midterm pregnant rats (7). In both the renal (7) and systemic circulations (present study), there was total abrogation of the gestational changes by neutralization or elimination of circulating relaxin indicating the absence of other contributing or compensatory mechanisms. In addition, the osmoregulatory changes were either totally (7) or largely prevented (current study). Whether relaxin also contributes to the cardiovascular and osmoregulatory changes in late pregnancy is currently under investigation.

The decline in SVR and increase in global AC during pregnancy can be attributed, at least in part, to a reduction in vascular smooth muscle tone (1). Another contribution may come from maternal angiogenesis (18). Interestingly, relaxin has been shown to exhibit angiogenic attributes (9, 19, 20). In the renal circulation, the gestational decline in renal vascular resistance is mediated through up-regulation of vascular gelatinase by relaxin that, in turn, mediates the conversion of big endothelin to endothelin1–32, thereby activating the endothelial ETB receptor/nitric oxide vasodilatory pathway (19, 21, 22). It is likely that this overall pathway also contributes to the decline in systemic vascular resistance during pregnancy; although different mechanisms in other circulatory beds, most notably vascular smooth muscle hyperpolarization, are also likely to contribute (23, 24).

The increase in vascular gelatinase observed during pregnancy or after administration of recombinant human relaxin (rhRLX) to nonpregnant rats led us to consider that, in addition to reducing vascular smooth muscle tone, the increased vascular gelatinase activity may also induce arterial remodeling. Vascular gelatinase activity has been implicated in vascular remodeling through degradation of extracellular matrix proteins such as collagen and elastin (25). We postulated that both the reduction in smooth muscle tone and arterial remodeling could contribute to the increase in global AC in vivo during pregnancy, and after relaxin administration to nonpregnant rats (9). This hypothesis was supported by our previous work in which nonpregnant rats administered rhRLX where characterized by both an increase in global AC and a decrease in SVR, as well as alterations in the passive mechanical properties of isolated renal arteries (9). Specifically, the isolated renal arteries from the rhRLX-treated rats were less stiff (or more compliant) than those from control animals. Thus, we expected to observe alterations in the passive mechanical properties of arteries from the midterm pregnant rats in the present study. However, there were no differences in the passive mechanical properties of small renal and larger mesenteric arteries isolated from virgin and gravid rats; nor did the relaxin neutralizing or control antibodies impact arterial passive mechanics.

There are several potential explanations for the observed lack of effects on vascular passive properties. First, rat relaxin is not as potent as human relaxin. Therefore, although circulating levels of rat relaxin during midterm pregnancy are sufficient to reduce arterial tone, they may be inadequate to affect vascular remodeling. Indeed, previous work has shown that human relaxin is more potent than rat relaxin in the isolated rat atria chronotropy bioassay (26). Bearing this in mind, the increase in global AC observed in midterm pregnant rats appears to be primarily attributable to reduction in vascular smooth muscle tone and not to arterial remodeling; however, we cannot exclude an increase in blood vessel density at this stage of pregnancy as a contributing factor. It should be noted that circulating levels of relaxin are considerably higher during late gestation in the rat. Therefore, arteries isolated from late-pregnant rats may be less stiff or more compliant. Indeed, previous reports indicated that renal and mesenteric arteries isolated from late-pregnant rats exhibit both reduced passive stiffness and tone (27, 28). Another possibility is that there are counterregulatory factors circulating during pregnancy (vs. the administration of rhRLX alone to nonpregnant rats) that offset the vascular remodeling properties of endogenous relaxin at least during midgestation.

Although heart rate tended to increase in the midterm pregnant rats administered either the MCA1 relaxin neutralizing or MCAF control antibodies compared with virgin animals, the differences did not reach statistical significance. This trend for an increase in heart rate during midterm pregnancy in conscious rats has been reported previously (4, 6, 29, 30). In our earlier work, we showed that rhRLX administered to nonpregnant rats exerted a modest, but significant chronotropic response. However, the augmentation of stroke volume by rhRLX contributed to a greater extent to the increase in cardiac output (9, 10). The failure to see a significant increase in heart rate in midterm pregnant rats may again relate to the lower potency of rat relaxin compared with rhRLX (26). Indeed, there are significant increases in heart rate during late rat gestation when the levels of endogenous circulating relaxin are at their highest (4, 5, 6, 29, 30).

One potential limitation is that we did not assess the influence of the MCA1 rat relaxin neutralizing antibodies in virgin rats. However, relaxin is not known to circulate in nonpregnant rats (5), and in previous work, we showed that the antibodies had no affect on renal blood flow, glomerular filtration rate, renal vascular resistance or plasma osmolality in virgin rats (7). Thus, it is highly unlikely that the MCA1 antibodies would affect systemic hemodynamics or arterial compliance in virgin rats, and given the expense of the antibodies ($300–400 per rat), we elected not to test the possibility.

To summarize, in the present study we show that circulating relaxin mediates the changes in systemic hemodynamics and global arterial compliance during midterm pregnancy in conscious rats. In contrast to our previous results with exogenous administration of human recombinant relaxin to nonpregnant rats, passive mechanics of renal and mesenteric arteries was unchanged during midterm pregnancy and after antibody administration. Thus, the increase in global AC observed in midterm pregnant rats may to be primarily attributable to reduction in smooth muscle tone and not to vascular wall remodeling.


   Acknowledgments
 
We thank Dr. David Sherwood for the rat relaxin neutralizing and control antibodies as well as his critical review of the manuscript.


   Footnotes
 
This project was supported by the National Institutes of Health (NIH) RO1 HL67937 and McGinnis Chair Endowment funds. D.O.D. was supported by a predoctoral fellowship award from the NIH (F31 HL79882).

Portions of this work were presented in abstract form (Debrah DO, Conrad KP, Novak J, Matthews JE, Ramirez RJ, Shroff SG, J Soc Gynecol Invest 13:380, February 2006).

Disclosure Statement: D.D., J.N., J.M. and R.R. have nothing to declare. S.S. and K.C. hold use patent(s) for relaxin.

First Published Online July 27, 2006

Abbreviations: AC, Arterial compliance; CO, cardiac output; LSD, least significant difference; MAP, mean arterial pressure; MCA1, neutralizing antibodies against rat relaxin; MCAF, control antibodies against fluorescein; PP, pulse pressure; rhRLX, recombinant human relaxin; {sigma}-{epsilon}, stress-strain; SV, stroke volume; SVR, systemic vascular resistance.

Received May 1, 2006.

Accepted for publication July 6, 2006.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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