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

## TL;DR

Testosterone levels in male and female rats with high blood pressure affect brain gene activity, linking sex hormones to hypertension.

## Contribution

This study reveals how testosterone influences gene expression in the paraventricular nucleus of hypertensive rats, highlighting sex-specific effects.

## Key findings

- High testosterone levels correlate with higher blood pressure in both male and female rats.
- Testosterone depletion in males regulates 5,104 genes in the PVN, many related to hormone signaling.
- Testosterone replacement in females regulates 1,727 genes, overlapping with genes in high-testosterone males.

## Abstract

Hypertension 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.

SHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10 mg 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.

in 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.

T status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome.

The online version contains supplementary material available at 10.1186/s13293-025-00818-0.

High blood pressure, or hypertension, is a common condition that affects both men and women equally over a lifetime, but men are typically at a higher risk for developing the disease earlier. The brain plays an important role to control blood pressure, specifically in a region of the hypothalamus known as the paraventricular nucleus (PVN). The PVN regulates blood pressure by controlling hormones. The study looks at how male and female rats with naturally high blood pressure respond when their testosterone levels are changed. This is done by removing organs related to testosterone production in some male rats, while some female rats were given more testosterone. We then observed the effect of varying testosterone levels in the male and female rats on the PVN. We found high testosterone levels were linked to higher blood pressure in both male and female rats. Removing testosterone in male rats was linked to 5, 104 differently expressed genes in the PVN relating to hormone signaling. Female rats given more testosterone were linked to 1,727 differently expressed genes, with many of these genes overlapping with the genes differentially expressed in male rats with high testosterone. These results show testosterone levels can strongly influence blood pressure regulation and alter gene activity in the brain, highlighting the connection between sex hormones and hypertension.

The online version contains supplementary material available at 10.1186/s13293-025-00818-0.

Testosterone levels correlate with mean arterial pressure (MAP) in male and female spontaneously hypertensive rats (SHRs)Manipulating testosterone via orchidectomy or supplementation in SHRs alters thousands of genes in the paraventricular nucleus (PVN), including genes associated with hormone and steroid signalling pathwaysRNA sequencing identified 6,571 differentially regulated genes between sexes, 5,104 genes after testosterone depletion in males, and 1,727 genes after testosterone replacement in females

Testosterone levels correlate with mean arterial pressure (MAP) in male and female spontaneously hypertensive rats (SHRs)

Manipulating testosterone via orchidectomy or supplementation in SHRs alters thousands of genes in the paraventricular nucleus (PVN), including genes associated with hormone and steroid signalling pathways

RNA sequencing identified 6,571 differentially regulated genes between sexes, 5,104 genes after testosterone depletion in males, and 1,727 genes after testosterone replacement in females

The online version contains supplementary material available at 10.1186/s13293-025-00818-0.