SUN-266 - Effect of Early to Mid-Gestational Testosterone Excess on the Sheep Aorta

Gestational testosterone (T) excess leads to hypertension and pathological cardiac remodeling in adult female sheep. However, the contribution of vascular defects, their ontogeny, progression, and the underlying mechanisms that drive this adverse programming remain unknown. We hypothesize that T excess will lead to sex specific adverse programming of the vasculature as early as fetal life, thereby disrupting vascular function postnatally in a sex specific manner. Pregnant ewes were intramuscularly injected with T propionate twice weekly from gestational days (GD) 30-90 (term 147). Two cohorts were generated: fetal (FC) and postnatal (PC). Aortas were harvested at GD 120 (30 days after cessation of T treatment) from FC and processed for molecular and histological analysis (n=6-7/sex/group). In the PC, serial blood pressures (BP) were obtained from birth to 18 months of age, and aortas (n=4-6/sex/group) were processed at 24 months for histological and molecular analysis. Data were analyzed using two-way ANOVA with sex-specific analyses in FC or sex-stratified t-tests in PC, and mixed-effects models for lifespan BP (p= 0.05 was considered significant, and Cohen’s d >0.80 was considered a large effect size). Prepubertal and adult gestational T-treated males (TM) had significantly lower BP, rather than significantly higher, compared with gestational T-treated females (TF) and their sex-specific controls. In the FC aortas, relative to their sex-specific controls, T induced a) a non-significant large effect size decrease in aortic medial thickness in males and not females, b) a significant treatment effect increase in apoptosis (TUNEL positive) in both sexes, and c) a treatment significance, large effect size increase in collagen deposition in both sexes d) disruption in cyclooxygenase (COX) proteins with a significant treatment effect and large effect size decrease in COX-1 protein in males, and no change in COX-2; in contrast, in females, COX-1 was unchanged, with a non-significant, large-effect-size increase in COX-2. In the PC aorta, T induced a) a non-significant large effect size increase in aortic medial thickness and media-to-lumen ratio in females and not males, b) a non-significant large effect size increase in apoptosis in females and not males, with no difference in collagen deposition c) a non-significant large effect size decrease in cyclooxygenase-1 (COX-1) protein in females and not males. In summary, excess T induced sex-specific alterations in BP postnatally. The adverse vascular effects of gestational T excess were evident in fetal life and persisted into the postnatal period, indicating a programming rather than an activational effect of gestational T exposure. Further research is needed to clarify the precise molecular mechanisms behind testosterone's adverse programming of the aortas.

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