title: STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective.
abstract: Previous studies have elucidated a neuroendocrine mechanism consisting of the hypothalamus (growth hormone releasing hormone, GHRH) - pituitary (growth hormone, GH) - STAT5a/b axis that underlies sex-biased gene expression in the liver. It is now established that male vs female patterned secretion of GHRH, and thus of circulating GH levels ("pulsatile" vs "more continuous" respectively), leading to differently patterned activation of PY-STAT5a/b in hepatocytes results in sex-biased gene expression of cohorts of hundreds of downstream genes. This review outlines new data in support of a STAT5a/b-based mechanism of sex bias in the vascular disease pulmonary hypertension (PH). Puzzling observations in PH include its 2-4-fold higher prevalence in women but a male-dominance in many rodent models, and, paradoxically, inhibition of PH development by estrogens in such models. We observed that conditional deletion of STAT5a/b in vascular smooth muscle cells (SMC) in mice converted the male-dominant model of chronic hypoxia-induced PH into a female-dominant phenotype. In human idiopathic PH, there was reduced STAT5a/b and PY-STAT5 in cells in late-stage obliterative pulmonary arterial lesions in both men and women. A juxtaposition of the prior liver data with the newer PH-related data drew attention to the hypothalamus-GH-STAT5 axis, which is the major target of estrogens at the level of the hypothalamus. This hypothesis explains many of the puzzling aspects of sex bias in PH in humans and rodent models. The extension of STAT5-anchored mechanisms of sex bias to vascular disease emphasizes the contribution of central neuroendocrine processes in generating sexual dimorphism in different tissues and cell types.
authors.affiliation: Departments of Cell Biology & Anatomy; New York Medical College; Valhalla, NY USA; Department of Medicine; New York Medical College; Valhalla, NY USA.
authors.forename: Pravin B
authors.initials: PB
authors.lastname: Sehgal
authors.affiliation: Departments of Cell Biology & Anatomy; New York Medical College ; Valhalla, NY USA.
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Yang
authors.affiliation: Departments of Cell Biology & Anatomy; New York Medical College ; Valhalla, NY USA.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Center for Heart and Lung Research; The Feinstein Institute for Medical Research ; Manhasset, NY USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
keywords: BCL6; STAT5a and STAT5b; arcuate nucleus; growth hormone; hypothalamus; neuroendocrine mechanisms; pulmonary hypertension, sex and gender bias; vascular disease; women's health