Pregnancy upregulates angiotensin type 2 receptor expression and increases blood flow in uterine arteries of rats†

Abstract

Normal pregnancy is associated with decreased uterine vascular contraction and increased blood flow even though angiotensin II (AngII) levels are increased. AngII not only activates the angiotensin type 1 receptor (AT1R) to mediate vasoconstriction but also angiotensin type 2 receptor (AT2R) to cause vasodilation. We hypothesized that upregulation of AT2R expression and function accounts for increased uterine artery blood flow during pregnancy. Virgin, pregnant rats at different days of gestation and post-partum Sprague-Dawley rats were used to determine uterine artery hemodynamics using micro ultrasound and plasma angiotensin II levels by ELISA. Isolated uterine arteries were examined for AT1R and AT2R expression and isometric contraction/relaxation. Plasma AngII levels were steady up to mid-pregnancy, increased as pregnancy advanced, reaching a peak in late pregnancy, and then restored to pre-pregnant levels after delivery. The pattern of increase in AngII levels mirrored a parallel increase in uterine blood flow. AT1R expression did not change but AT2R expression increased during pregnancy correlating with uterine blood flow increase. Treatment with the AT2R antagonist PD123319 reduced uterine arterial blood flow. Vasoconstriction to angiotensin II was blunted in pregnant rats. Treatment with PD123319 caused greater enhancement of AngII contraction in pregnant than virgin rats. Ex vivo exposure of estradiol to uterine arterial rings dose dependently upregulated AT2R expression, that was inhibited by estrogen receptor antagonist. These results demonstrate that elevated AngII levels during gestation induces increase in uterine blood flow via heightened AT2R-mediated signaling. Estrogens appear to directly upregulate uterine vascular AT2R independent of any endogenous factors.

Distinct uterine artery gene expression profiles during early gestation in the stroke-prone spontaneously hypertensive rat

“…Examining the uteroplacental vascular gene expression in these early remodelling stages is key for understanding the vascular responses to HDP. Studies have examined the differential gene expression over gestation in humans and rodents and found pregnancydependent changes in the expression of hormone receptors, calcium and potassium channels and growth factors in the uterine artery (13,(18)(19)(20). However, studies examining the genetic profile of the uterine arteries response to pathophysiological pregnancy are lacking.…”

Angiotensin II Type 2 Receptor: A Target for Protection Against Hypertension, Metabolic Dysfunction, and Organ Remodeling

“…Estradiol exposure leads to the upregulation of AT 2 R expression, which is inhibited by the ERα antagonist. 74 This study suggests that AT 2 R expression and function are increased during pregnancy and may play a role in attenuating BP-related complications. A similar conclusion was revealed by another study in an AT 1 a knockout mouse model.…”

“…Estrogen supplementation restored the AT 2 R expression to normal, 68 , 69 likely via the activation of ERα, as demonstrated by the ERα-knockout mice model and AT 2 R antagonist treatment. 74 , 75 In contrast, ERβ (not ERα) is upregulated in pregnancy and binds with and transactivates ER-responsive elements in the AT 2 R promoter in the uterine arteries of pregnant mice; this effect was mediated by ERα in nonpregnant mice. 72 This finding suggests a shift towards ERβ/AT 2 R-mediated BP regulation in pregnancy.…”

Neurohormonal and Pharmacological Regulation of Oestrogen, Progesterone, Luteinizing Hormone and Follicle Stimulating Hormone Over the Menstrual Cycle – The Possible Relevance of Angiontensin Ii

“…In the mammary glands, progesterone together with oestradiol stimulates the proliferation and secretory arrangement of the pulmonary alveoli [9,10]. Although studies in mice and rats suggest that progesterone reduces the frequency of the GnRH (gonadotropin-releasing hormone) pulse in 2 to 6 hours [20], the corresponding human data are mixed: some studies suggest rapid slowing (within 8 -14 h) [11], while others suggest that longer progesterone exposure is needed [28]. Among the pituitary hormones, the follicle stimulation hormone (FSH) and luteinizing hormone (LH) are studied.…”