Human uterine and placental arteries exhibit tissue-specific acute responses to 17β-estradiol and estrogen-receptor-specific agonists

Abstract

The discrete regulation of vascular tone in the human uterine and placental circulations is a key determinant of appropriate uteroplacental blood perfusion and pregnancy success. Humoral factors such as estrogen, which increases in the placenta and maternal circulation throughout human pregnancy, may regulate these vascular beds as studies of animal arteries have shown that 17β-estradiol, or agonists of estrogen receptors (ER), can exert acute vasodilatory actions. The aim of this study was to compare how acute exposure to ER-specific agonists, and 17β-estradiol, altered human placental and uterine arterial tone in vitro. Uterine and placental arteries were isolated from biopsies obtained from women with uncomplicated pregnancy delivering a singleton infant at term. Vessels were mounted on a wire myograph, exposed to the thromboxane receptor agonist U46619 (10(-6) M), and then incubated with incremental doses (5 min, 0.03-30 µM) of either 17β-estradiol or agonists specific for the ERs ERα (PPT), ERβ (DPN) or the G-protein-coupled estrogen receptor GPER-1 (G1). ERα and ERβ mRNA expression was assessed. 17β-estradiol, PPT and DPN each relaxed myometrial arteries (P < 0.05) in a manner that was partly endothelium-dependent. In contrast, 17β-estradiol or DPN relaxed placental arteries (maximum relaxation to 42 ± 1.1 or 47.6 ± 6.53% of preconstriction, respectively) to a lesser extent than myometrial arteries (to 0.03 ± 0.03 or 8.0 ± 1.0%) and in an endothelial-independent manner whereas PPT was without effect. G1 exposure did not inhibit the constriction of myometrial nor placenta arteries. mRNA expression of ERα and ERβ was greater in myometrial arteries than placental arteries. ER-specific agonists, and 17β-estradiol, differentially modulate the tone of uterine versus placental arteries highlighting that estrogen may regulate human uteroplacental blood flow in a tissue-specific manner.

Keywords: ER agonists; estrogen; human placental arteries; human uterine arteries; vascular tone.

Figure 1

Differential effects of 17β-estradiol and ER agonists on human myometrial and placental arteries. Myometrial (A–D) or placental (E–H) arteries were preconstricted with U46619 and exposed to incremental doses of estrogenic compounds. Representative raw tracings are displayed in A–C, E–G, summary data (mean ± SEM, n = 6) in D and H. 17β-estradiol or ERβ agonist, DPN relaxed myometrial arteries to a greater extent than placental arteries whereas ERα agonist, PPT relaxed only myometrial arteries. GPER-1 agonist (G1) was without effect in either artery type. *Significant differences from time control (TC).

Figure 2

Relaxatory actions of estrogenic compounds are partly endothelial- and NO-dependent in human myometrial arteries. The relaxation of preconstricted myometrial arteries by 17β-estradiol (A), PPT (B) or DPN (C) was blunted following endothelial abrasion (open symbols, dashed lines) or by pretreatment with nitric oxide synthase inhibitor (L-NNA) (open symbols, solid lines). *Significant differences from intact artery responses. Data are presented as mean ± SEM (n = 6).

Figure 3

Vasodilatory actions of estrogenic compounds are endothelial-independent in human placental arteries. The relaxation of preconstricted placental arteries by 17β-estradiol or DPN were unaltered by endothelial abrasion (A) or by pretreatment with L-NNA (B). Data are presented as mean ± SEM (n = 6).

Figure 4

ER expression in human arteries. Expression of mRNA encoding for ERα (A) or ERβ (B). ERα mRNA expression was greater in myometrial arteries (MA) than placental arteries (PA). Western blotting indicated that ER expression was greater in myometrial than placental arteries (C and D). PC, refers to the positive control of human myometrium. *Significant differences between MA and PA.

Figure 5

Vasodilatory effects of estrogenic compounds are unrelated to changes in Ca²⁺-sensitization of contraction but are enhanced in the presence of an L-type Ca²⁺ channel agonist. Permeabilized placental arteries exhibited U46619-induced Ca²⁺-sensitization of contraction at sub-maximal activating Ca²⁺ (pCa6.7) that was similar in magnitude to contraction in pCa4.5 solution alone (representative raw data tracing of A). 17β-estradiol (30 µM) did not affect this agonist-mediated Ca²⁺-sensitization. In intact preconstricted placental arteries, 17β-estradiol-mediated relaxation (B) was enhanced by preincubation with the L-type Ca²⁺ channel agonist Bay K8644 (C and D). Similar effects were observed on DPN-mediated relaxation (D). *Significant differences between 17β-estradiol alone and in the presence of Bay K8644.