STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

Abstract

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.

A comprehensive contribution of genetic variations of the insulin-like growth factor 1 signalling pathway to stroke susceptibility

“…The GHRH-GH-IGF1 system promoted vascular smooth muscle cell (VSMC) proliferation and migration and was required for normal vascular reactivity and remodelling [34]. Thereby, sexual differentiation of GHRH expression contributed to the difference in the patterns of GH and IGF1 secretion between men and women, and it may result in sex bias in vascular remodelling [35].…”

Smooth Muscle-Specific BCL6+/− Knockout Abrogates Sex Bias in Chronic Hypoxia-Induced Pulmonary Arterial Hypertension in Mice

“…This is a higher sexual dimorphism ratio than that for estradiol-17 β (E2) (ratio: 2.2-fold female bias) or testosterone (ratio: 14-fold male bias) observed in the same sera [ 25 ]. Mice and rats also show similar quantitative differences in the respective male versus female patterns of circulating GH ([ 26 – 29 ], reviewed in [ 21 ]) ( Figure 1 ). Male rodents show discrete GH pulses approximately every 3–5 hr with little or no circulating GH detectable during the interpulse interval, while in female rats, the pulses are more frequent, the pulse heights are lower, and the interpulse levels are relatively low but nonzero [ 26 – 29 ].…”

“…The mechanisms that determine this sexual dimorphism in humans are incompletely understood. Puzzlingly, several studies have pointed to a direct protective effect of estrogens on development of an equivalent pulmonary arterial hypertension (PAH) disease process in experimental animals (such as in mice and rats exposed to chronic hypoxia or in rats exposed to monocrotaline pyrrole) ([ 9 – 21 ], and citations therein). Thus, in these experimental models in mice and rats it is the males that preferentially develop more pronounced disease, while exogenously administered estrogens have proven to be protective.…”

“…In attempting to understand the mechanistic basis of this species-dependent sex-bias paradox (higher incidence of IPAH in women, but greater susceptibility to PAH in male mice and rats, with exogenous estrogens having a protective effect) [ 9 – 18 ], we discovered that smooth muscle cells (SMCs) in obliterative IPAH lesions in humans had a marked reduction in levels of the sex-responsive transcription factors STAT5a and STAT5b (collectively either “STAT5a/b” or “STAT5”), their activated Tyr-phosphorylated entities (PY-STAT5), and a downstream sex-responsive target of STAT5—the “broad-spectrum” transcriptional repressor B-cell lymphoma 6 protein (BCL6) ( Figure 1 ) [ 19 – 21 ]. This discovery focused our attention on the possibility that the resolution of the species-specific sex-bias paradox in PAH between human females (greater susceptibility to PAH than males) and rodent females (lesser susceptibility to PAH than males) might reside in the well-known differences in the patterns of sex-biased secretion of growth hormone (GH)—a well-characterized upstream activator of STAT5a/b [ 19 – 21 ]. Women have a high baseline level of GH with small frequent peaks (a pattern referred to as “more continuous”), while men have a low baseline with few but high level peaks of GH (a pattern referred to as “pulsatile”) ([ 20 – 29 ], and citations therein) ( Figure 1 ).…”

“…Women have a high baseline level of GH with small frequent peaks (a pattern referred to as “more continuous”), while men have a low baseline with few but high level peaks of GH (a pattern referred to as “pulsatile”) ([ 20 – 29 ], and citations therein) ( Figure 1 ). Thus, circulating GH levels in men comprise 2–4 peaks per day with very low interpulse levels, while in women there is a higher frequency of pulses (>7 peaks/day) with significantly elevated interpulse levels ( Figure 1 ) ([ 22 – 25 ]; reviewed in [ 20 , 21 ]). Even when assayed at a single time-point in humans (in the morning after fasting), the median value of serum GH levels was 80–120-fold higher in young adult women than in young adult men [ 25 ].…”