Altered Endothelin Receptor Binding in Response to Nitric Oxide Synthase Inhibition in the Pregnant Rat

Neerhof, Mark G.; Jilling, Tamás; Synowiec, Sylvia; Khan, Saira; Thaete, Larry G.

doi:10.1177/1933719107312627

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…Activation of ET A is known to induce prostaglandin production in decidua. 35,36 HOXA10 directly induces expression of prostaglandin receptors as well as prostaglandin production through ET A . This leads to the establishment of a system that has the coordinated ability to both produce and respond to prostaglandins.…”

Section: Discussionmentioning

confidence: 99%

Endothelin Type A Receptor (ETA) Expression Is Regulated by HOXA10 in Human Endometrial Stromal Cells

Penna

Kallen

et al. 2010

Reprod. Sci.

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Endothelin type A receptor (ETA) is a member of the superfamily of G protein-coupled receptors. Our laboratory conducted a microarray screen that identified ETA as target of HOXA10 transcriptional control in endometrium. Here, we confirm HOXA10-regulated ETA expression in endometrium. Endometrial biopsies were obtained from fertile reproductive-age individuals, and first trimester decidual samples were obtained at the time of elective termination. Immunohistochemistry (IHC) was used to identify ETA protein in endometrium as well as first trimester decidua. ETA was expressed in endometrial stromal cells throughout the menstrual cycle. ETA was also highly expressed in first trimester decidual cells. The regulatory relationship between HOXA10 and ETA was established by transient transfection analysis. The human endometrial stromal cell line (HESC) and the human endometrial epithelial cell line (Ishikawa) were transfected with pcDNA/HOXA10, HOXA10 small interfering RNA (siRNA), or respective controls. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to determine expression levels of HOXA10 and ETA in each group. ETA gene expression increased 9-fold (P < .05) after pcDNA/HOXA10 transfection of HESC. ETA was not regulated by HOXA10 in Ishikawa cells. We conclude that ETA is expressed in normal endometrium and decidua. Expression of this receptor is regulated by an essential mediator of endometrial receptivity, HOXA10. ETA may enhance the proliferative potential of endometrial cells in a manner similar to that seen in vascular smooth muscle cells. ETA likely acts as a molecular mechanism by which HOXA10 promotes stromal cell growth and prostaglandin production in both the implantation window and decidua.

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Section: Discussionmentioning

confidence: 99%

Endothelin Type A Receptor (ETA) Expression Is Regulated by HOXA10 in Human Endometrial Stromal Cells

Penna

Kallen

et al. 2010

Reprod. Sci.

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“…The binding affinity of ET A is increased as NO is reduced. 15 Mechanistically, NO can bind the ET A cysteine cluster and modify receptor affinity, 16 therefore decreased NO can lead to increased ET A receptor affinity.…”

Section: Introductionmentioning

confidence: 99%

Endothelin Receptor A Antagonism and Fetal Growth in Endothelial Nitric Oxide Synthase Gene Knockout Maternal and Fetal Mice

2016

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Fetal growth restriction (FGR) is commonly associated with perinatal morbidity and mortality. Nitric oxide (NO) deficiency increases endothelin-1 (ET-1) production, and this increased ET-1 may contribute to the pathophysiology of NO deficiency-induced FGR. Using an endothelial NO synthase knockout mouse model of FGR, we sought to determine (a) the relative importance of maternal versus conceptus (fetal and placental) NO deficiency and (b) the contribution of ET-1 to the pathogenesis of FGR in this model. Fetal growth restriction occurred both with NO-deficient conceptuses in the setting of maternal NO production and with maternal NO deficiency in the setting of NO-producing conceptuses. Placental ET-1 expression was increased in NO-deficient dams, ET receptor A (ETA) production increased in endothelial nitric oxide synthase(+/-) placentas, and antagonism of ETA prevented FGR. These results demonstrate that both maternal and conceptus NO deficiency can contribute to FGR and suggest a role for ETA antagonists as therapeutic agents in FGR.

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“…Further, NO decreases the affinity of ET A for its ligand, displacing bound ET-1 (16–18). With reduced NO in the setting of NOS inhibition, the affinity of ET A for ET-1 is increased (19). …”

Section: Introductionmentioning

confidence: 99%

“…NOS inhibition from day 14 to 21 of the 22-day gestation results in decreased uterine and placental perfusion, decreased fetal and placental growth, and an increase in maternal circulating ET-1 (10,11,15,19–21). In the setting of chronic NOS inhibition, administration of a mixed ET A /ET B antagonist does not improve fetal or placental growth or placental perfusion at any time during administration (10).…”

Section: Introductionmentioning

confidence: 99%

Impact of Endothelin A Receptor Antagonist Selectivity in Chronic Nitric Oxide Synthase Inhibition-Induced Fetal Growth Restriction in the Rat

Neerhof

Synowiec

Khan

et al. 2010

Hypertension in Pregnancy

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Objective Endothelin receptor A (ETA) antagonism improves fetal and placental growth and placental perfusion on days 1 and 4, but not day 7 of a 7-day infusion of a nitric oxide synthase (NOS) inhibitor. Our purpose was to evaluate the significance of the degree of ETA antagonist selectivity on uteroplacental perfusion and fetal growth on day 7 of chronic NOS inhibition. Methods Timed-pregnant rats were treated with the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg/h) with and without one of the following ETA antagonists or their respective vehicles for 7 days beginning on day 14 of gestation: A-127722 (2,000-fold selective for ETA over ETB), FR139317 (8,000-fold ETA-selective), or ABT-546 (28,000-fold ETA-selective). Uterine and placental perfusion, as well as fetal and placental weight, was evaluated at the 7th day of treatment (gestation day 21). Results L-NAME administration resulted in a significant reduction in uterine and placental perfusion as well as fetal and placental growth. In the setting of NOS inhibition, ETA antagonism did not improve uterine or placental perfusion or fetal growth after 7 days of infusion irrespective of the degree of selectivity of the antagonist used. Conclusions ETA antagonism, irrespective of the degree of receptor selectivity, does not improve fetal growth or uteroplacental perfusion on day 7 of chronic NOS inhibition.

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Altered Endothelin Receptor Binding in Response to Nitric Oxide Synthase Inhibition in the Pregnant Rat

Cited by 4 publications

References 25 publications

Endothelin Type A Receptor (ETA) Expression Is Regulated by HOXA10 in Human Endometrial Stromal Cells

Endothelin Type A Receptor (ETA) Expression Is Regulated by HOXA10 in Human Endometrial Stromal Cells

Endothelin Receptor A Antagonism and Fetal Growth in Endothelial Nitric Oxide Synthase Gene Knockout Maternal and Fetal Mice

Impact of Endothelin A Receptor Antagonist Selectivity in Chronic Nitric Oxide Synthase Inhibition-Induced Fetal Growth Restriction in the Rat

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