Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Mair, Kirsty M.; Xu, Yang; Lü, Long; White, Kevin P.; Wallace, Emma; Ewart, Marie-Ann; Docherty, Craig K.; Morrell, Nicholas W.; MacLean, Margaret R.

doi:10.1164/rccm.201410-1802oc

Cited by 68 publications

(95 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, these genes show retention of sex bias in their expression (25). Correspondingly, female-derived PASMCs proliferate modestly faster in response to 5-HT, PDGF or BMP4 (25). These observations are similar to the findings of Thangavel et al (67), who observed that GH-mediated inducibility of male-biased isoforms of cytochrome P450 was better when cultures were derived from male rats but not female rats.…”

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

confidence: 83%

“…Thus, these genes show retention of sex bias in their expression (25). Correspondingly, female-derived PASMCs proliferate modestly faster in response to 5-HT, PDGF or BMP4 (25).…”

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

confidence: 97%

“…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%

“…Ninth, in primary human pulmonary artery smooth muscle cells (PASMCs) in culture (from disease-free individuals), the expression of BMPR2, Id1 and Id3 but not Smad1 are higher in male-derived cells compared with female-derived cells (25). Thus, these genes show retention of sex bias in their expression (25).…”

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

confidence: 99%

See 4 more Smart Citations

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

Sehgal

Yang

Miller

2015

Mol Med

View full text Add to dashboard Cite

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.

show abstract

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

confidence: 83%

“…Thus, these genes show retention of sex bias in their expression (25). Correspondingly, female-derived PASMCs proliferate modestly faster in response to 5-HT, PDGF or BMP4 (25).…”

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

confidence: 97%

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%

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

View full text Add to dashboard Cite

show abstract

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Hester

Ventetuolo

Lahm

2019

Comprehensive Physiology

118

View full text Add to dashboard Cite

Pulmonary hypertension (PH) encompasses a syndrome of diseases that are characterized by elevated pulmonary artery pressure and pulmonary vascular remodeling and that frequently lead to right ventricular (RV) failure and death. Several types of PH exhibit sexually dimorphic features in disease penetrance, presentation, and progression. Most sexually dimorphic features in PH have been described in pulmonary arterial hypertension (PAH), a devastating and progressive pulmonary vasculopathy with a 3-year survival rate <60%. While patient registries show that women are more susceptible to development of PAH, female PAH patients display better RV function and increased survival compared to their male counterparts, a phenomenon referred to as the "estrogen paradox" or "estrogen puzzle" of PAH. Recent advances in the field have demonstrated that multiple sex hormones, receptors, and metabolites play a role in the estrogen puzzle and that the effects of hormone signaling may be time and compartment specific. While the underlying physiological mechanisms are complex, unraveling the estrogen puzzle may reveal novel therapeutic strategies to treat and reverse the effects of PAH/PH. In this article, we (i) review PH classification and pathophysiology; (ii) discuss sex/gender differences observed in patients and animal models; (iii) review sex hormone synthesis and metabolism; (iv) review in detail the scientific literature of sex hormone signaling in PAH/PH, particularly estrogen-, testosterone-, progesterone-, and dehydroepiandrosterone (DHEA)-mediated effects in the pulmonary vasculature and RV; (v) discuss hormone-independent variables contributing to sexually dimorphic disease presentation; and (vi) identify knowledge gaps and pathways forward.

show abstract

Serotonin and Pulmonary Hypertension; Sex and Drugs and ROCK and Rho

MacLean¹,

Fanburg²,

Hill³

et al. 2022

Comprehensive Physiology

View full text Add to dashboard Cite

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Cited by 68 publications

References 44 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

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Serotonin and Pulmonary Hypertension; Sex and Drugs and ROCK and Rho

Contact Info

Product

Resources

About