Publication Date

2015

Journal Title

Mol Med

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 2-4-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 [e.g. estradiol-17beta (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 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 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") vs female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male vs female patterned activation of STAT5a/b in peripheral tissues, and thus sex-biased expression of hundreds of genes. In this essay we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

Document Type

Article

EPub Date

2015/08/08

Status

Faculty

Facility

School of Medicine

Primary Department

Molecular Medicine

Additional Departments

Medicine; Surgery

PMID

26252185

DOI

10.2119/molmed.2015.00122


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