The serotonin transporter, gender, and 17  oestradiol in the development of pulmonary arterial hypertension

White, Kevin P.; Dempsie, Yvonne; Nilsen, Margaret; Wright, Audrey F.; Loughlin, Lynn; MacLean, Margaret R.

doi:10.1093/cvr/cvq408

Cited by 100 publications

(146 citation statements)

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“…We note that all previous work on sex bias in rodent-based PH models, including after administration of steroid sex hormones (for example, E2, 2-ME or testosterone) and/or gonadectomy, have focused on direct effects of steroid hormones at the level of peripheral vascular tissues in the lung (5,6,8,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). (However, the terminology used can often be confusing and, indeed, misleading.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…Thus, in the context of a "neuroendocrine hypothesis," the term "central" refers to the hypothalamus and pituitary [the "neuro-" part], while the terms "distal" or "peripheral" refer to all locations in the body where a hormone can circulate [the "-endocrine" part]). Thus, there have been extensive studies of steroid hormone effects (E2, 2-ME, testosterone) in lung tissues in rodent models, in isolated human and rodent pulmonary vascular cells (smooth muscle cells [SMCs] and endothelial cells [ECs]) and on vascular cell proliferation, transcriptional regulation of BMPR2 gene expression and BMPR2-initiated cell signaling (5,6,8,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This exclusive focus on peripheral tissue effects of steroid hormones is somewhat at odds with insights gleaned over the last 30-40 years in a sister field (sex-biased expres- Figure 1.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…Seventh, why do female mice overexpressing the serotonin transporter or the S100 calcium-binding protein S100A4/mts1 or the dexfenfluramineadministered mice, but not male mice, develop modest PH by 5 months (15,(19)(20)(21)(22)? Although increased serotonin (5-HT) has been implicated in the pathogenesis of PH (10,15,26,100), especially in the femalespecific mouse models developed by MacLean et al (19)(20)(21), and after administration of an anorectic drug dexfenfluramine (22,100), the mechanistic focus has largely been on effects of 5-HT on distal vascular tissues (10,15,19-22,26,100).…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

“…Although increased serotonin (5-HT) has been implicated in the pathogenesis of PH (10,15,26,100), especially in the femalespecific mouse models developed by MacLean et al (19)(20)(21), and after administration of an anorectic drug dexfenfluramine (22,100), the mechanistic focus has largely been on effects of 5-HT on distal vascular tissues (10,15,19-22,26,100). We note that it is already known that the PHcausing anorexigens fenfluramine, aminorex, phentermine and fluoxetine increase 5-HT in the hypothalamus (101)(102)(103)(104)(105) and that fenfluramine blunted GH responsiveness to GHRH (105).…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

“…In contrast, the phrase "sex biased" refers to entities that show a quantitative phenotypic difference between the two sexes.) In converse examples, female mice overexpressing the serotonin transporter or the S100 calcium-binding protein S100A4/mts1, or administered the anorexigen dexfenfluramine (but not male mice), spontaneously develop modest PH by 5 months (15,(19)(20)(21)(22). Although only up to one-third of male mice expressing the BMPR2 R899X transgene spontaneously developed right ventricular systolic pressure >30 mmHg, this proportion increased to two-thirds when the mice were fed a high-fat diet (23); in this model, 2-ME was not protective (24).…”

Section: Introductionmentioning

confidence: 99%

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Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Role of miR‐21‐5p/FilGAP axis in estradiol alleviating the progression of monocrotaline‐induced pulmonary hypertension

Qian

Zhao

et al. 2022

Anim Models and Exp Med

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Background: Aberrant expression of microRNAs (miRNAs) has been associated with the pathogenesis of pulmonary hypertension (PH). It is, however, not clear whether miRNAs are involved in estrogen rescue of PH.Methods: Fresh plasma samples were prepared from 12 idiopathic pulmonary arterial hypertension (IPAH) patients and 12 healthy controls undergoing right heart catheterization in Shanghai Pulmonary Hospital. From each sample, 5 μg of total RNA was tagged and hybridized on microRNA microarray chips. Monocrotaline-induced PH (MCT-PH) male rats were treated with 17β-estradiol (E 2 ) or vehicle. Subgroups were cotreated with estrogen receptor (ER) antagonist or with antagonist of miRNA.Results: Many circulating miRNAs, including miR-21-5p and miR-574-5p, were markedly expressed in patients and of interest in predicting mean pulmonary arterial pressure elevation in patients. The expression of miR-21-5p in the lungs was significantly upregulated in MCT-PH rats compared with the controls. However, miR-574-5p showed no difference in the lungs of MCT-PH rats and controls. miR-21-5p was selected for further analysis in rats as E 2 strongly regulated it. E 2 decreased miR-21-5p expression in the lungs of MCT-PH rats by ERβ. E 2 reversed miR-21-5p target gene FilGAP downregulation in the lungs of MCT-PH rats. The abnormal expression of RhoA, ROCK2, Rac1 and c-Jun in the lungs of MCT-PH rats was inhibited by E 2 and miR-21-5p antagonist.Conclusions: miR-21-5p level was remarkably associated with PH severity in patients.Moreover, the miR-21-5p/FilGAP signaling pathway modulated the protective effect of E 2 on MCT-PH through ERβ.

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Lung Circulation

Suresh

Shimoda

2016

Comprehensive Physiology

104

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The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed.

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The serotonin transporter, gender, and 17 oestradiol in the development of pulmonary arterial hypertension

Cited by 100 publications

References 40 publications

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Role of miR‐21‐5p/FilGAP axis in estradiol alleviating the progression of monocrotaline‐induced pulmonary hypertension

Lung Circulation

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