Role of the AT2 receptor in modulating the angiotensin II contractile response of the uterine artery at mid-gestation

Abstract

Introduction: During human pregnancy, circulating concentrations of components of the renin-angiotensin system increase, but pressor refractoriness to angiotensin II (Ang-II) is observed. Given the importance of the Ang-II pressor response in deciding susceptibility to preeclampsia and of the Ang-II system for controlling uterine vasoreactivity, we sought to address the effects of pregnancy on the reactivity of the isolated uterine artery (UA) in mice.

Materials and methods: Blood pressure was measured throughout pregnancy in awake C57BL/6J mice. UA segments were isolated from three groups of animals (non-pregnant, mid [day 12-13] and late [day 18-19] gestation) and studied by wire myography.

Results: UA diameters, KCl-mediated responses, and acetylcholine-dependent vasorelaxation were greater at mid and late gestation than in non-pregnant animals. Ang-II responses were also greater during pregnancy, with an increased contraction in response to AT2 receptor blockade at mid-gestation. AT1 receptor blockade abolished the Ang-II response in all groups.

Conclusions: Study findings are consistent with the possibility that AT2 receptor-mediated vasodilatation plays a role in modulating Ang-II contractile responses in pregnancy.

Figure 1

Systolic blood pressure (SBP; A) and heart rate (HR; B) in non-pregnant (NP, n=6), mid gestation (MG, n=11) and late gestation (LG, n=7) pregnant mice. Dotted vertical line indicates day of breeding. C and D: Data correspond to the average of 4 days for NP (white box), days 12 and 13 for MG (black box) and days 18 and 19 for LG (gray box). Data are shown as mean±SEM. *p<0.05 vs NP and LG, †p<0.05 vs LG by ANOVA.

Figure 2

Potassium chloride (KCl)-induced (A) and U46619-induced (B) vasoconstriction in uterine arteries from non-pregnant (NP, n=5), mid gestation (MG, n=8) and late gestation (LG, n=7) mice. Responses are expressed as absolutes values of tension (AWT; arterial wall tension) in N/m (A) or as % of maximal KCl response (%K_MAX, B). Data are shown as mean±SEM. *p<0.05 vs NP, †p<0.05 vs MG, in maximal response by ANOVA.

Figure 3

Acetylcholine-induced relaxation in NP, MG and LG uterine arteries pre-constricted with 3x10⁻⁸ M U46619. Responses are expressed as percentage of the contraction response. A; response in control arteries. B; response in arteries pre-treated with 10⁻⁴M L-NAME. Data are shown as mean±SEM. *p<0.05 vs NP by ANOVA.

Figure 4

Maximal contractile responses of isolated uterine artery (UA) during mouse pregnancy. Absolute maximal responses to KCl, U46619 and Ang-II expressed as mN/mm² in nonpregnant (NP, n=5), midgestation (MG, n=8) and late gestation (LG, n=7). Data are shown as mean±SEM. # p<0.05 vs NP values, *p<0.05 vs MG, †p<0.05 vs KCl.

Figure 5

Contractile response to Ang-II in mouse UA. A. Representative trace showing the response to Ang-II in UA of a control pregnant mice at mid-gestation compared to the response to 62.5 mM KCl (w=wash). B. Absolute maximal response to Ang-II expressed as mN/mm² in control arteries, arteries pre-treated with PD123319 10⁻⁵ M and arteries pre-treated with losartan 10⁻⁵ M as indicated, in NP (n=5), MG (n=8) and LG (n=7) groups. Data are shown as mean±SEM. *p<0.05 vs MG control, †p<0.05 vs control and PD123319 treated arteries by ANOVA.