Vasorelaxing effects of estetrol in rat arteries

Abstract

This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E 4 ) vs 17b-estradiol (E 2 ) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentrationresponse curves (CRCs) to E 4 and E 2 (0 . 1-100 mmol/l) were constructed. In all arteries tested, E 4 had lower potency than E 2 , although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1 mmol/l) caused a significant rightward shift in the CRC to both E 4 and E 2 , indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases by N u -nitro-L-arginine methyl ester (L-NAME) blunted E 2 -mediated but not E 4 -mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E 4 or E 2 in uterine arteries. Combined blockade of NO release and action with L-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E 4 compared with E 2 in uterine arteries. Endothelium denudation inhibited responses to both E 4 and E 2 , while E 4 and E 2 concentration-dependently blocked smooth muscle cell Ca 2C entry in K C -depolarized and Ca 2C -depleted uterine arteries. In conclusion, E 4 relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E 4 -induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca 2C entry, but not NO synthases or endothelium-dependent hyperpolarization.

Non-genomic actions of sex hormones on pregnant uterine contractility in rats: An in vitro study at term

“…It was proved that E2 and P4 had a vasorelaxant action through a non-genomic pathway. Studies on rat arterial beds showed that E2 induced vascular relaxation [17]. The same results were found on the arterial tissues in human [18,19] lamb [20], monkey [21] and mice [12].…”

Effect of Oxidative Stress on the Estrogen-NOS-NO-KCa Channel Pathway in Uteroplacental Dysfunction: Its Implication in Pregnancy Complications

“…IKs and SKs are also expressed in VSMCs of uterine and placental chorionic plate arteries in addition to their expression in ECs [90, 107]. In the uteroplacental system, IKs and SKs participated in the regulation of contractility of uterine and placental vessels [90, 107, 109]. Moreover, SK3 was also involved in regulating uterine vascular remodeling and placental vascularization [110, 111].…”

Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells

“…3 Discovered by Diczfalusy in 1965, 4 the precise effects of E 4 on various tissues during pregnancy remain unknown. A series of recent studies elucidated various tissue-specific properties of E 4 including differential effects on brain, 5 the vascular nitrous oxide system, 6 and membrane actions as opposed to nuclear. 7 Estetrol was identified as a potential drug for human use by Coelingh Bennink in 2001.…”