Endothelin type A receptor antagonist attenuates placental ischemia–induced hypertension and uterine vascular resistance

Tam, Kiran B. Tam; George, Eric M.; Cockrell, Kathy; Arany, Marietta; Speed, Joshua S.; Martin, James N.; LaMarca, Babbette; Granger, Joey P.

doi:10.1016/j.ajog.2011.01.049

Cited by 58 publications

(37 citation statements)

References 26 publications

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“…ET A R is mainly expressed in vascular smooth muscle cells (VSMCs) to induce vasoconstriction, whereas ET B R is predominately expressed in endothelial cells (ECs) to induce the release of vasodilator substances as well as aiding ET-1 clearance [13]. ET A R was previously considered to be primarily responsible for pregnancy-induced hypertension (PIH), and it has been shown that blocking ET A R attenuates PIH [14, 15]. However, ET B R upregulation in VSMCs was also found to be associated with many cardiovascular diseases and to contribute to vasoconstriction [13, 16-19].…”

Section: Introductionmentioning

confidence: 99%

Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension

Sun

Zhang

Chen

et al. 2017

Cell Physiol Biochem

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Background/Aims: Studies have shown that a change in endothelin receptor expression in the artery is related to pregnancy-induced hypertension (PIH). However, the mechanism underlying this change remains unclear. Methods: To test whether the distribution of endothelin receptor type-A (ET_AR) and type-B (ET_BR) plays an important role in PIH, a reduction of uterine perfusion pressure (RUPP) rat model was used to mimic some of the features of PIH; the resulting variable endothelin receptor expression was investigated in the media and intima of the aorta. Single vascular smooth muscle cells (VSMCs) were isolated from RUPP and normal pregnant (NP) rats to study the effect of ET_AR and ET_BR in smooth muscle cells. Results: Compared with NP rats, RUPP rats had a significant redistribution of ET_BR expression in the intima and media, while there was no significant difference in ET_AR expression between the two groups. ET_BR upregulation in VSMCs enhanced cellular contraction and contributed to PIH. The TNF-α plasma levels in RUPP rats were two-fold higher than those of NP rats, which upregulated the expression of ET_BR in VSMCS through the NF-κB pathways in RUPP rats. Conclusion: Redistribution of ET_BR between the media and intima played an important role in the pathogenesis of PIH.

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Section: Introductionmentioning

confidence: 99%

Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension

Sun

Zhang

Chen

et al. 2017

Cell Physiol Biochem

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“…15,35 Studies have shown that treatment of RUPP rats with an ET A R antagonist decreases BP, and suggested a role for ET A R in HTN-Preg. 13,18,24,36 However, the decreased BP in RUPP rats treated with ET A R antagonist can also be explained by the possibility that most ET-1 would be directed towards endothelial ET B R to promote vasodilation, and thus made it important to examine the role of vascular ET B R in normotensive and HTN-Preg.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Microvascular Endothelial Type B Endothelin Receptor Is a Central Vascular Mechanism in Hypertensive Pregnancy

Mazzuca

Reslan

et al. 2014

Hypertension

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Preeclampsia is a pregnancy-related disorder characterized by hypertension (HTN) with unclear mechanism. Studies have shown endothelial dysfunction and increased endothelin-1 (ET-1) levels in hypertensive-pregnancy (HTN-Preg). ET-1 activates endothelin receptor type-A (ETAR) in vascular smooth muscle to induce vasoconstriction, but the role of vasodilator endothelial ETBR in the changes in blood pressure (BP) and vascular function in HTN-Preg is unclear. To test if downregulation of endothelial ETBR expression/activity plays a role in HTN-Preg, BP was measured in Norm-Preg rats and rat model of HTN-Preg produced by reduction of uteroplacental perfusion pressure (RUPP), and mesenteric microvessels were isolated for measuring diameter, [Ca2+]i, and ETAR and ETBR levels. BP, ET-1 and KCI-induced vasoconstriction and [Ca2+]i were greater in RUPP than Norm-Preg rats. Endothelium-removal or microvessel treatment with ETBR antagonist BQ-788 enhanced ET-1 vasoconstriction and [Ca2+]i in Norm-Preg, but not RUPP, suggesting reduced vasodilator ETBR in HTN-Preg. ET-1+ETAR antagonist BQ-123, and ETBR agonists sarafotoxin 6c (S6c) and IRL-1620 caused less vasorelaxation and nitrate/nitrite production in RUPP than Norm-Preg. The NOS inhibitor L-NAME reduced S6c- and IRL-1620-induced relaxation in Norm-Preg but not RUPP, supporting that ETBR-mediated NO pathway is compromised in RUPP. RT-PCR, Western blots and immunohistochemistry revealed reduced endothelial ETBR expression in RUPP. Infusion of BQ-788 increased BP in Norm-Preg, and infusion of IRL-1620 reduced BP and ET-1 vasoconstriction and [Ca2+]i and enhanced ETBR-mediated vasorelaxation in RUPP. Thus downregulation of microvascular vasodilator ETBR is a central mechanism in HTN-Preg, and increasing ETBR activity could be a target in managing preeclampsia.

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“…When an ET A receptor antagonist was administered to the RUPP rats, the associated hypertension was abolished, and there was a trend for improved renal function [20]. Tam Tam et al also reported that pretreatment with ET A attenuates both the mean arterial pressure (MAP) and uterine artery resistance index (UARI) in the RUPP group without affecting these parameters in the normal pregnant group [53]. The improvement in UARI could be one potential mechanism for the reduction in MAP in response to ET A in pregnant dams with ischemic placentas.…”

Section: The Et System In Pementioning

confidence: 99%

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

2018

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Purpose of Review Preeclampsia (PE) is a disorder of pregnancy typically characterized by new-onset hypertension and proteinuria after gestational week 20. Although preeclampsia is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disorder remain unclear and treatment options are limited. Placental ischemic events and the release of placental factors appear to play a critical role in the pathophysiology. These factors contribute to a generalized systemic vascular endothelial dysfunction and result in increased systemic vascular resistance and hypertension. Recent Findings There is increasing evidence to suggest that endothelin-1 (ET-1) in the maternal vascular endothelium is a critical final common pathway, whereby placental ischemic factors cause cardiovascular and renal dysfunction in the mother. Multiple studies report increased levels of ET-1 in PE. A number of experimental models of PE are also associated with elevated tissue levels of prepro-ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 excess, TNF-α excess, and AT1-AA infusion) have proven to be responsive to ET type A receptor antagonism. Recent studies also suggest that abnormalities in ET type B receptor signaling may also play a role in PE. Summary Although numerous studies highlight the importance of the ET system in the pathogenesis of PE, further work is needed to determine whether ET receptor antagonists could provide an effective therapy for the management of this disease.

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Endothelin type A receptor antagonist attenuates placental ischemia–induced hypertension and uterine vascular resistance

Cited by 58 publications

References 26 publications

Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension

Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension

Downregulation of Microvascular Endothelial Type B Endothelin Receptor Is a Central Vascular Mechanism in Hypertensive Pregnancy

The Endothelin System: A Critical Player in the Pathophysiology of Preeclampsia

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