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

Abstract

The “estrogen paradox” in pulmonary arterial hypertension (PAH) refers to observations that while there is a higher incidence of idiopathic PAH in women, rodent models of PAH show male dominance and estrogens are protective. To explain these differences, we previously proposed the neuroendocrine-STAT5-BCL6 hypothesis anchored in the sex-biased and species-specific patterns of growth hormone (GH) secretion by the pituitary, the targeting of the hypothalamus by estrogens to feminize GH secretion patterns, and the role of the transcription factors STAT5a/b and BCL6 as downstream mediators of this patterned GH-driven sex bias. As a test of this hypothesis, we previously reported that vascular smooth muscle cell- (SMC-) specific deletion of the STAT5a/b locus abrogated the male-dominant sex bias in the chronic hypoxia model of PAH in mice. In the present study, we confirmed reduced BCL6 expression in pulmonary arterial (PA) segments in both male and female SMC:STAT5a/b−/− mice. In order to test the proposed contribution of BCL6 to sex bias in PAH, we developed mice with SMC-specific deletion of BCL6+/− by crossing SM22α-Cre mice with BCL6-floxed mice and investigated sex bias in these mutant mice in the chronic hypoxia model of PAH. We observed that the male-bias observed in wild-type- (wt-) SM22α-Cre-positive mice was abrogated in the SMC:BCL6+/− knockouts—both males and females showed equivalent enhancement of indices of PAH. The new data confirm BCL6 as a contributor to the sex-bias phenotype observed in hypoxic PAH in mice and support the neuroendocrine-STAT5-BCL6 hypothesis of sex bias in this experimental model of vascular disease.

Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension

“…Second, in this study, all mice and rats we studied were males and it is known that females have increased incidence of PH. 28,32 Third, CO and EF values were calculated from LV, not from RV. Thus, using rats with hypoxia exposure only as another control for the hypoxia sugen group, studying female animals and measuring CO and EF values from RV in these rodent models of PH may warrant our further echocardiographic studies.…”

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

“…Compared with rats, mice are relatively resistant to HPH regardless of sex (126,161,406). Nevertheless, female HPH mice also display more favorable hemodynamics, less RV hypertrophy, and less PA remodeling (478,479). While favorable hemodynamics and decreased RV hypertrophy are akin to humans, decreased PA remodeling is not.…”