Drastic Shift From Positive to Negative Estrogen Effect on Bone Morphogenetic Protein Signaling in Pulmonary Arterial Endothelial Cells Under Hypoxia

Ichimori, Hiroaki; Kogaki, Shigetoyo; Takahashi, Kyoko; Ishida, Hidekazu; Narita, Jun; Nawa, Nobutoshi; Baden, Hiroki; Uchikawa, Toshiki; Okada, Yôko; Ozono, Keiichi

doi:10.1253/circj.cj-12-0997

Cited by 11 publications

(4 citation statements)

References 39 publications

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“…The effects of estrogen (and other sex hormones) are also likely to be cell/ tissue-specific and context-specific. For example, the effects of estradiol on BMP signaling in endothelial cells have been shown to shift from augmentation to inhibition when studied under normoxic versus hypoxic conditions, respectively (7). In addition, studies in BMPR2 mutation carriers have highlighted the importance of active estrogen metabolites other than 2-OHE and 2-ME in mediating increased PAH penetrance.…”

mentioning

confidence: 99%

The Imitation Game in Pulmonary Arterial Hypertension. Sex, Bone Morphogenetic Protein Receptor, and the Estrogen Paradox

Singla¹,

Machado²

2015

Am J Respir Crit Care Med

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Estimating ground-level PM2.5 in China using satellite remote sensing. Environ Sci Technol 2014;48: 7436-7444. 16. Brunekreef B, Janssen NA, de Hartog J, Harssema H, Knape M, van Vliet P. Air pollution from truck traffic and lung function in children living near motorways. Epidemiology 1997;8:298-303. 17. Morales E, Garcia-Esteban R, de la Cruz OA, Basterrechea M, Lertxundi A, de Dicastillo MD, Zabaleta C, Sunyer J. Intrauterine and early postnatal exposure to outdoor air pollution and lung function at preschool age. Thorax 2015;70:64-73. 18. Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly. Am J Respir Crit Care Med 2014;190: 542-548. Bone morphogenetic protein receptor type 2 (BMPR2) mutations account for approximately 75% of hereditary pulmonary arterial hypertension (HPAH) cases and 25% of sporadic idiopathic PAH cases (1). Although BMPR2 mutations are inherited in an autosomal-dominant fashion, the penetrance of these mutations in HPAH is only approximately 30% (1). This incomplete penetrance strongly suggests the presence of additional genetic and/or environmental disease-modifying factors. Interestingly, in BMPR2 mutation carriers, the female penetrance is around 40%, whereas male penetrance is around 14% (2). Multiple studies have demonstrated that the prevalence of idiopathic PAH and HPAH is significantly higher in females (reviewed by Umar and colleagues [3] and Austin and colleagues [4]). In contrast, when compared with women, men with PAH have worse right ventricular function and survival, and in the monocrotaline and hypoxia (but not in the SU5416/hypoxia) rodent models of PH, female sex has a protective effect (reviewed by Umar and colleagues [3] and Austin and colleagues [4]).Efforts to reconcile this "estrogen paradox" (3, 4) have revealed a complex interplay between multiple facets of estrogen metabolism and BMP signaling, as well as limitations of rodent models of PH. The vascular protective effects of estradiol in experimental PH appear to be largely regulated by its nonestrogenic metabolites, 2-hydroxyestriadiol (2-OHE) and 2-methoxyestrone (2-ME). Both of these metabolites have been shown to attenuate monocrotaline-induced PH as well as hypoxiainduced PH in male rats (5, 6). 2-ME also abolishes the mortality induced by ovariectomy in monocrotaline PH (6). The effects of estrogen (and other sex hormones) are also likely to be cell/ tissue-specific and context-specific. For example, the effects of estradiol on BMP signaling in endothelial cells have been shown to shift from augmentation to inhibition when studied under normoxic versus hypoxic conditions, respectively (7). In addition, studies in BMPR2 mutation carriers have highlighted the importance of active estrogen metabolites other than 2-OHE and 2-ME in mediating increased PAH penetrance. West et al first demonstrated significantly decreased transcript levels of CYPB1, a cytochrome p450 family enzyme critical to estrogen metaboli...

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confidence: 99%

The Imitation Game in Pulmonary Arterial Hypertension. Sex, Bone Morphogenetic Protein Receptor, and the Estrogen Paradox

Singla¹,

Machado²

2015

Am J Respir Crit Care Med

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“…Moreover, there is direct binding of ERα to EREs on the promoter of the BMPR2 gene, resulting in estrogen-mediated reductions in BMPR2 expression (142). In addition, changes in oxygen concentration can alter E2 effects on BMP signaling in human PAECs (146).…”

Section: Vascular Remodelingmentioning

confidence: 99%

Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension

Sun

Sangam

Guo

et al. 2021

Front. Cardiovasc. Med.

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Pulmonary arterial hypertension (PAH) is a complex and devastating disease with a poor long-term prognosis. While women are at increased risk for developing PAH, they exhibit superior right heart function and higher survival rates than men. Susceptibility to disease risk in PAH has been attributed, in part, to estrogen signaling. In contrast to potential pathological influences of estrogen in patients, studies of animal models reveal estrogen demonstrates protective effects in PAH. Consistent with this latter observation, an ovariectomy in female rats appears to aggravate the condition. This discrepancy between observations from patients and animal models is often called the “estrogen paradox.” Further, the tissue-specific interactions between estrogen, its metabolites and receptors in PAH and right heart function remain complex; nonetheless, these relationships are essential to characterize to better understand PAH pathophysiology and to potentially develop novel therapeutic and curative targets. In this review, we explore estrogen-mediated mechanisms that may further explain this paradox by summarizing published literature related to: (1) the synthesis and catabolism of estrogen; (2) activity and functions of the various estrogen receptors; (3) the multiple modalities of estrogen signaling in cells; and (4) the role of estrogen and its diverse metabolites on the susceptibility to, and progression of, PAH as well as their impact on right heart function.

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“…11 Ichimori et al 10 proposed that HIF-1α may play a role in regulating BMP/Smads signals. They also revealed the crosstalk between estrogen and BMP signals, which was previously demonstrated in other types of the cells.…”

Section: New Insight Into the Estrogen Paradoxmentioning

confidence: 99%

The Challenge of the “Estrogen Paradox” in Pulmonary Arterial Hypertension

Yamauchi–Takihara

2013

Circ J

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Drastic Shift From Positive to Negative Estrogen Effect on Bone Morphogenetic Protein Signaling in Pulmonary Arterial Endothelial Cells Under Hypoxia

Cited by 11 publications

References 39 publications

The Imitation Game in Pulmonary Arterial Hypertension. Sex, Bone Morphogenetic Protein Receptor, and the Estrogen Paradox

The Imitation Game in Pulmonary Arterial Hypertension. Sex, Bone Morphogenetic Protein Receptor, and the Estrogen Paradox

Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension

The Challenge of the “Estrogen Paradox” in Pulmonary Arterial Hypertension

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