Figure 1

Hypothesis: central neuroendocrine and peripheral mechanisms in generation of sex bias in PH. Male (M: “pulsatile”) versus female (F: “more continuous”) patterned secretion of GH by the pituitary followed by patterned activation of the STAT5a/b-BCL6 axis represents a well-established pathway (27) to functionally connect the hypothalamus/pituitary on the one hand and pulmonary vascular tissues on the other hand as a mechanism for generating sex-biased gene expression in the latter. Upstream of pituitary/GH would be multifactorial central sex-bias mechanisms that impinge on the hypothalamus and effectuate M versus F patterns of secretion of GHRH; these include estradiol-17β (E2), serotonin (5-HT), cytokines and BMPs. Downstream of STAT5-BCL6 in peripheral pulmonary vascular cells would be hundreds of responsive genes for which patterned expression together contributes to the sex-biased disease process involving cell proliferation, cell hypertrophy, resistance to apoptosis and cytokine/growth factor secretion. The hypothesis also includes direct effects of various mediators (for example, cytokines and growth factors) at the level of the peripheral pulmonary vascular cells in a sex- and species-biased manner due to underlying gene expression changes (of on the order of perhaps 500–1,000 genes) already effectuated through the GH-STAT5 axis.