Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia

Stanhewicz, Anna E.; Jandu, Sandeep; Santhanam, Lakshmi; Alexander, Lacy M.

doi:10.1042/cs20171292

Cited by 27 publications

(28 citation statements)

References 59 publications

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“…Recently, our laboratory examined vasoconstrictor responses to ET-1 in the cutaneous microvasculature of women who had preeclampsia. In agreement with the animal findings, we found that formerly preeclamptic women had an exaggerated vasoconstrictor response to ET-1, mediated by dysregulation of the ET B R (83). When compared with women who had a normal pregnancy, women with a history of preeclampsia had reduced ET B R-mediated dilation, and, in fact, ET B R signaling contributed to vasoconstriction, presumably through increased ET B R protein expression in the vascular smooth muscle (Fig.…”

Section: Endothelin-1 Signalingsupporting

confidence: 89%

Residual vascular dysfunction in women with a history of preeclampsia

Stanhewicz

2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Preeclampsia is a hypertensive disorder of pregnancy characterized by new onset hypertension, proteinuria, and edema occurring after 20 weeks of gestation, with a prevalence of ~7-10% of pregnancies in the United States and ~8 million pregnancies worldwide. Despite the postpartum remission of preeclamptic symptoms, women who have had preeclampsia are 2-4 times more likely to develop cardiovascular disease (CVD) and are significantly more likely to die of CVD compared to women with a history of normal pregnancy. While the relation between history of preeclampsia and elevated CVD risk is well documented, the mechanism(s) underlying this association remain unclear. One hypothesis explaining this association is that the initial vascular damage and dysfunction sustained during the preeclamptic pregnancy persists chronically. Indeed, even in the absence of, or in advance of overt CVD women who have had preeclampsia have compromised vascular endothelial function. Emerging mechanistic studies in these women have provided some insight into the underlying mechanisms of this persistent vascular dysfunction and have begun to identify potential therapeutic targets for the prevention or mitigation of CVD progression in this vulnerable population. This review summarizes the existing literature examining vascular function and dysfunction in women with a history of preeclampsia, and highlights future directions for mechanistic investigations and development of novel intervention strategies aimed at halting or slowing the progression of CVD in these women.

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Section: Endothelin-1 Signalingsupporting

confidence: 89%

Residual vascular dysfunction in women with a history of preeclampsia

Stanhewicz

2018

American Journal of Physiology-Regulatory, Integrative and Comp

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“…28 Although women with preeclampsia appear asymptomatic after delivering the placenta, an underlying dysfunction in the blood vessels remains. 30 Women with a history of preeclampsia had a MACE in the 10 years following the birth in an affected pregnancy of 18.2% compared with 1.7% of women without preeclampsia. 32 A recent meta-analysis comprising 22 studies and over six million women concluded that preeclampsia was associated with a fourfold increase in future incident heart failure and a twofold increased risk of MACE.…”

Section: Preeclampsiamentioning

confidence: 98%

“…29 One study on microvascular dysfunction found that ET-1-mediated vasoconstriction was increased in the microvasculature of women with a history of preeclampsia. 30 This may be attributed to the absence of ET-1 receptor type-Bmediated dilation, leading to an exaggerated vasoconstrictive response to ET-1. 30 Flow-mediated dilation is also abnormal with preeclampsia.…”

Section: Preeclampsiamentioning

confidence: 99%

“…30 This may be attributed to the absence of ET-1 receptor type-Bmediated dilation, leading to an exaggerated vasoconstrictive response to ET-1. 30 Flow-mediated dilation is also abnormal with preeclampsia. Chambers et al 31 compared women with healthy pregnancies to women with a history of preeclampsia, with a median interval of 3 years postpartum.…”

Section: Preeclampsiamentioning

confidence: 99%

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Microvascular Disease and Small-Vessel Disease: The Nexus of Multiple Diseases of Women

Patel

Aggarwal

Rao

et al. 2020

Journal of Women's Health

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Microvascular disease, or small-vessel disease, is a multisystem disorder with a common pathophysiological basis that differentially affects various organs in some patients. The prevalence of small-vessel disease in the heart has been found to be higher in women compared with men. Additionally, other diseases prominently affecting women, including heart failure with preserved ejection fraction, Takotsubo cardiomyopathy, cerebral small-vessel disease, preeclampsia, pulmonary arterial hypertension (PAH), endothelial dysfunction in diabetes, diabetic cardiomyopathy, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, may have a common etiologic linkage related to microvascular disease. To the best of our knowledge this is the first article to investigate this potential linkage. We sought to identify various diseases with a shared pathophysiology involving microvascular/endothelial dysfunction that primarily affect women, and their potential implications for disease management. Advanced imaging technologies, such as magnetic resonance imaging and positron-emission tomography, enable the detection and increased understanding of microvascular dysfunction in various diseases. Therapies that improve endothelial function, such as those used in PAH, may also be associated with benefits across the full spectrum of microvascular dysfunction. A shared pathology across multiple organ systems highlights the need for a collaborative, multidisciplinary approach among medical subspecialty practitioners who care for women with small-vessel disease. Such an approach may lead to accelerated research in diseases that affect women and their quality of life.

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“…Systemic and uterine vasculature are refractory to vasoconstrictions during pregnancy. In contrast, enhanced contractile responses to vasoconstrictors is a characteristic feature of preeclampsia ( Naden & Rosenfeld 1981 , Magness & Rosenfeld 1986 , Benoit et al 2007 , Stanhewicz et al 2017 ). Elevated testosterone during pregnancy is shown to enhance contractile responses to many vasoconstrictors in endothelium-intact vessels, but in endothelium-denuded vessels, there is enhanced contractile response specific to angiotensin II in rat mesenteric ( Chinnathambi et al 2014 b ) and uterine arteries ( Chinnathambi et al 2014 a ).…”

Section: Testosterone-induced Mechanisms Of Vascular Dysfunction Durimentioning

confidence: 99%

Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis

et al. 2018

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Adequate maternal vascular adaptations and blood supply to the uterus and placenta are crucial for optimal oxygen and nutrient transport to growing fetuses of eutherian mammals, including humans. Multiple factors contribute to hemodynamics and structuring of placental vasculature essential for term pregnancy with minimal complications. In women, failure to achieve or sustain favorable pregnancy progression is, not surprisingly, associated with high incidence of antenatal complications, including preeclampsia, a hypertensive disorder of pregnancy. While the pathogenesis of preeclampsia in women remains unknown, a role for androgens is emerging. The relationship between androgens and maternal cardiovascular and placental function deserves particular consideration because testosterone levels in the circulation of preeclamptic women are elevated approximately two- to three-fold and are positively correlated with vascular dysfunction. Preeclampsia is also associated with elevated placental androgen receptor (AR) gene expression. Studies in animal models mimicking the pattern and level of increase of adult female testosterone levels to those found in preeclamptic pregnancies, replicate key features of preeclampsia, including gestational hypertension, endothelial dysfunction, exaggerated vasoconstriction to angiotensin II, reduced spiral artery remodeling, placental hypoxia, decreased nutrient transport and fetal growth restriction. Taken together, these data strongly implicate AR-mediated testosterone action as an important pathway contributing to clinical manifestation of preeclampsia. This review critically addresses this hypothesis, taking into consideration both clinical and preclinical data.

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Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia

Cited by 27 publications

References 59 publications

Residual vascular dysfunction in women with a history of preeclampsia

Residual vascular dysfunction in women with a history of preeclampsia

Microvascular Disease and Small-Vessel Disease: The Nexus of Multiple Diseases of Women

Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis

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