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

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 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.

Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension

“…The hyper and hypo-methylated promoters in PAH compared to controls were mainly associated with angiogenesis and vascular diseases (Figures 1B , 3A , Tables 2 , 3 , 4 ). We observed a dysfunction in the promoters DES, ETS2, TERT, MYH7, TBX1/5 playing a major role in heart contraction and morphogenesis [ 25 – 28 ] but also in promoters involved in inflammation and remodeling (growth factor and cytokines activities) such as TNFSF4, COL1A1 and FGF1 [ 29 , 30 ]. These results are in agreement with the central implication of inflammatory mechanisms in PAH [ 4 , 31 ].…”

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

“…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 ). 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 ]).…”

“…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 ].…”

“…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 ]. Overall, when compared to GH levels at peak pulse height, female humans have a relatively high interpulse level, while female rodents have a low interpulse level ([ 22 – 29 ]; reviewed in [ 20 , 21 ]). We have pointed to this difference in relative interpulse levels as a key difference between women and female rodents that might underlie the estrogen paradox [ 19 – 21 ].…”

“…We have pointed to this difference in relative interpulse levels as a key difference between women and female rodents that might underlie the estrogen paradox [ 19 – 21 ]. It is noteworthy that the pulsatility in GH levels is largely unconnected to the day-night circadian rhythms or the pulsatility of the cardiac cycle [ 20 – 29 ].…”