Exogenous Estrogen Preserves Distal Pulmonary Arterial Mechanics and Prevents Pulmonary Hypertension in Rats

Philip, Jennifer L.; Tabima, Diana M.; Wolf, Gregory D.; Frump, Andrea L.; Cheng, Tik-Chee; Schreier, David A.; Hacker, Timothy A.; Lahm, Tim; Chesler, Naomi C.

doi:10.1164/rccm.201906-1217le

Cited by 18 publications

(9 citation statements)

References 17 publications

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“…Importantly, in these experiments E2-repletion in ovariectomised female PH rats strongly reduced the development of PH, suggesting that E2 has protective effects on PH development in females. Similarly, PHILIP et al [58] confirmed that exogenous oestrogen treatment in Su/Hx-PH rats reduced PA vasoconstriction and remodelling after Su/Hx exposure. In addition, in Su/Hx rats, oestrogen treatment was found to protect RV function by preserving mitochondrial biogenesis, function and oxidative capacity, at least partially explaining the cardioprotective mechanism of oestrogens in female PH patients [59].…”

Section: Classical Models Of Experimental Phmentioning

confidence: 76%

Sex and gender in pulmonary arterial hypertension

et al. 2021

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Pulmonary arterial hypertension (PAH) is a rare disease characterised by pulmonary vascular remodelling and elevated pulmonary pressure, which eventually leads to right heart failure and death. Registries worldwide have noted a female predominance of the disease, spurring particular interest in hormonal involvement in the disease pathobiology. Several experimental models have shown both protective and deleterious effects of oestrogens, suggesting that complex mechanisms participate in PAH pathogenesis. In fact, oestrogen metabolites as well as receptors and enzymes implicated in oestrogen signalling pathways and associated conditions such as BMPR2 mutation contribute to PAH penetrance more specifically in women. Conversely, females have better right ventricular function, translating to a better prognosis. Along with right ventricular adaptation, women tend to respond to PAH treatment differently from men. As some young women suffer from PAH, contraception is of particular importance, considering that pregnancy in patients with PAH is strongly discouraged due to high risk of death. When contraception measures fail, pregnant women need a multidisciplinary team-based approach. This article aims to review epidemiology, mechanisms underlying the higher female predominance, but better prognosis and the intricacies in management of women affected by PAH.

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Section: Classical Models Of Experimental Phmentioning

confidence: 76%

Sex and gender in pulmonary arterial hypertension

et al. 2021

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“…There are contradictory preclinical studies investigating the role of estrogen on PAH pathogenesis as some studies suggest exogenous estrogen and/or its metabolites aggravate pulmonary vascular remodeling (White et al, 2011 ; Dempsie et al, 2013 ) while others show protective effects (Umar et al, 2011 ; Philip et al, 2020 ). The importance and potential reasoning underlying these divergent findings are expertly reviewed elsewhere (Lahm et al, 2014 ).…”

Section: Estrogen: the Predominant Female Sex Hormone's Potential Promentioning

confidence: 99%

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside

2021

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There are inherent distinctions in right ventricular (RV) performance based on sex as females have better RV function than males. These differences are magnified and have very important prognostic implications in two RV-centric diseases, pulmonary hypertension (PH), and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). In both PH and ARVC/D, RV dysfunction results in poor patient outcomes. However, there are no currently approved therapies specifically targeting the failing RV, an important unmet need for these two life-threatening disorders. In this review, we highlight human data demonstrating divergent RV phenotypes in healthy, PH, and ARVC/D patients based on sex. Furthermore, we discuss the links between estrogen (the female predominant sex hormone), testosterone (the male predominant sex hormone), and dehydroepiandrosterone (a precursor hormone for multiple sex hormones in males and females) and RV function in both disorders. To provide potential mechanistic insights into sex differences in RV function, we review data that investigate how sex hormones combat or contribute to pathophysiological changes in the RV. Finally, we highlight the ongoing clinical trials in pulmonary arterial hypertension targeting estrogen and dehydroepiandrosterone signaling. Hopefully, a greater understanding of the factors that promote superior RV function in females will lead to novel therapeutic approaches to combat RV dysfunction in PH and ARVC/D.

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“…In addition, E2 also affects mechanical properties of the pulmonary vasculature which in turn could affect RV structure and performance. In particular, E2 can increase both proximal as well as distal PA compliance, and, at least when given exogenously, also attenuate PA remodeling (75,77,78). It is currently unknown if E2's RV-protective effects are mediated by direct effects on RV-specific cell types or by more indirect effects resulting from reducing RV afterload.…”

Section: Sex Hormones and Their Effect On Rv Functionmentioning

confidence: 99%

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

Agrawal¹,

Lahm²,

Hansmann³

et al. 2020

Cardiovasc Diagn Ther

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Pulmonary arterial hypertension (PAH) is a rare, life-threatening condition characterized by dysregulated metabolism, pulmonary vascular remodeling, and loss of pulmonary vascular cross-sectional area due to a variety of etiologies. Right ventricular (RV) dysfunction in PAH is a critical mediator of both long-term morbidity and mortality. While combinatory oral pharmacotherapy and/or intravenous prostacyclin aimed at decreasing pulmonary vascular resistance (PVR) have improved clinical outcomes, there are currently no treatments that directly address RV failure in PAH. This is, in part, due to the incomplete understanding of the pathogenesis of RV dysfunction in PAH. The purpose of this review is to discuss the current understanding of key molecular mechanisms that cause, contribute and/or sustain RV dysfunction, with a special focus on pathways that either have led to or have the potential to lead to clinical therapeutic intervention. Specifically, this review discusses the mechanisms by which vessel loss and dysfunctional angiogenesis, sex hormones, and metabolic derangements in PAH directly contribute to RV dysfunction. Finally, this review discusses limitations and future areas of investigation that may lead to novel understanding and therapeutic interventions for RV dysfunction in PAH.

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Exogenous Estrogen Preserves Distal Pulmonary Arterial Mechanics and Prevents Pulmonary Hypertension in Rats

Abstract: 17b-estradiol (E2), the most abundant female sex steroid, has been implicated in the development and progression of pulmonary arterial hypertension (PAH) (1, 2). Although some studies have

Cited by 18 publications

References 17 publications

Sex and gender in pulmonary arterial hypertension

Sex and gender in pulmonary arterial hypertension

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism

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