The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats

Paterson, A.; Loh, S.-Y.; Gholami, S. K.; Rogers, M. F.; Murugan, D. D.; Lam, S.-K.; Mustafa, M. R.; Ott, B. P.; Balaratnam, P.; Mecawi, A. d. S.; Murphy, D.; Hindmarch, C. C.

doi:10.1101/2025.02.20.639267

bioRxiv · 10.1101/2025.02.20.639267

The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats

Paterson, A.·Loh, S.-Y.·Gholami, S. K.·Rogers, M. F.·Murugan, D. D.·Lam, S.-K.·Mustafa, M. R.·Ott, B. P.·Balaratnam, P.·Mecawi, A. d. S.·Murphy, D.·Hindmarch, C. C.

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Abstract

BackgroundHypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals. MethodsSHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis. ResultsIn total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate. ConclusionsT status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome

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Paterson, A., Loh, S.-Y., Gholami, S. K., Rogers, M. F., Murugan, D. D., Lam, S.-K., Mustafa, M. R., Ott, B. P., Balaratnam, P., Mecawi, A. d. S., Murphy, D., Hindmarch, C. C.. 2025-02-21. The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats. https://doi.org/10.1101/2025.02.20.639267

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