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Molecular Medicine

, Volume 21, Issue 1, pp 688–701 | Cite as

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

  • Pravin B. Sehgal
  • Yang-Ming Yang
  • Edmund J. Miller
Review Article

Abstract

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 well-characterized 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.

Notes

Acknowledgments

We thank Jana Velíšková for insightful neuroscience discussions. This work was supported, in part, by National Heart, Lung, and Blood Institute Grants HL-087176 (to PB Sehgal), HL-114509 (to PB Sehgal) and HL-111469 (to EJ Miller). We also thank the Pulmonary Hypertension Breakthrough Initiative (PHBI) for providing sections of human lung tissue studied in ref. (28) (adapted data illustrated, in part, in the present Figure 7); funding for PHBI was provided by the Cardiovascular Medical Research and Education Fund (CMREF).

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Authors and Affiliations

  • Pravin B. Sehgal
    • 1
    • 2
  • Yang-Ming Yang
    • 1
  • Edmund J. Miller
    • 3
  1. 1.Department of Cell Biology and AnatomyNew York Medical CollegeValhallaUSA
  2. 2.Department of MedicineNew York Medical CollegeValhallaUSA
  3. 3.Center for Heart and Lung ResearchThe Feinstein Institute for Medical ResearchManhassetUSA

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