Sex-specific hypothalamic PVN transcriptomic signatures of blood pressure autonomic regulation and neuroinflammation in hypertension

TL;DR

This study finds that male and female rats with high blood pressure have different brain gene patterns that may explain sex differences in hypertension.

Contribution

The study identifies sex-specific molecular pathways in the hypothalamus linked to hypertension and autonomic regulation.

Findings

Male hypertensive rats showed more differentially expressed genes and upregulated Bdnf and Agtr1a, linked to elevated blood pressure.

Female hypertensive rats exhibited anti-inflammatory gene profiles, including upregulated Nlrc3 and Pirb.

Both sexes shared neuroinflammation-related gene changes, such as downregulated Anxa1 and upregulated Slc11a1.

Abstract

Hypertension is a multifactorial condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus (PVN) plays a central role in blood pressure (BP) regulation by modulating sympathetic tone and releasing neuropeptides that affect the cardiovascular function. In this study, we investigated the transcriptomic profile of the PVN in hypertensive strains and across sexes, aiming to identify novel sex-specific molecular pathways involved in the regulation of BP.

To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR), both male and female. We also performed a cardiovascular assessment based on blood pressure (BP) measurements and their variability.

Cardiovascular assessment revealed higher SBP in SHRs than in Wistar rats; while males exhibited greater autonomic regulation associated with vasomotor and neurohumoral mechanisms, while females maintained comparable SBP levels primarily through an increase in heart rate, reflecting distinct autonomic adaptations. Hypertension also impacted gene expression, with influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs). Key upregulated genes in males, including Brain-Derived Neurotrophic Factor (Bdnf) and Hypocretin (Hcrt), have already been linked to elevated BP, and Angiotensin II Receptor Type 1 (Agtr1a) is possibly associated with increased SBP-VLF variability, which serves as an indirect measure of enhanced sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with upregulation of NLR Family CARD Domain Containing 3 (Nlrc3) and Paired Ig-like Receptor B (Pirb), and downregulation of Absent in Melanoma 2 (Aim2), and S100 Calcium Binding Protein B (S100b). Notably, genes associated with neuroinflammation, such as the downregulation of Annexin A1 (Anxa1) and the upregulation of Solute Carrier Family 11 Member 1 (Slc11a1), were consistently altered in both sexes.

These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting distinct neurohumoral autonomic profile in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.

The online version contains supplementary material available at 10.1186/s13293-026-00855-3.

Hypertension is a complex condition of unknown cause that affects more than 1.28 billion adults worldwide and impacts the sexes differently. The hypothalamic paraventricular nucleus plays a central role in blood pressure regulation by modulating sympathetic tone and releasing neuropeptides that affect blood pressure. In this study, we investigated the gene expression profile of the PVN in male and female Wistar rats and in Spontaneously Hypertensive Rats to identify the mechanisms involved in the regulation of blood pressure. RNA-sequencing analysis revealed that distinct gene expression profiles were influenced by sex and hypertensive conditions. We demonstrated that hypertensive male rats presented an increased number of differentially expressed genes, indicating a greater impact of hypertension on the paraventricular nucleus in males. The key upregulated genes in males include those previously linked in the literature to elevated blood pressure. In contrast, the female transcriptome was characterized by the upregulation of anti-inflammatory genes, which may mitigate brain inflammation in the paraventricular nucleus, potentially offsetting hypertensive mechanisms. Notably, genes associated with neuroinflammation were identified and found to be conserved between sexes. In conclusion, our data provide new insights into the key mechanisms underlying hypertension, as well as the sex differences of this condition. We demonstrated anti-inflammatory effects in females, which may help explain the lower prevalence of hypertension during the premenopausal period. These results offer a valuable framework for understanding the pathophysiology of hypertension and for developing future sex-specific therapeutic strategies.

The online version contains supplementary material available at 10.1186/s13293-026-00855-3.

Cardiovascular assessment confirmed elevated blood pressure in SHRs compared with Wistar rats, with male SHRs exhibiting a more pronounced vasomotor/neurohumoral autonomic profile than females, whereas females demonstrated a higher heart rate.Transcriptomic profiling of the PVN revealed a greater number of differentially expressed genes in male SHRs, underscoring the impact of hypertension in males.Consistent downregulation of Anxa1 and upregulation of Slc11a1 across both sexes highlights a potential shared mechanism of neuroinflammation in hypertensive states.Key upregulated genes in male SHRs, including Bdnf and Agtr1a, may increases the baseline BP and enhance the VLF component of BP variability as a central feature of the male transcriptomic profile.Compared with male SHRs, female SHRs exhibited an anti-inflammatory signature characterized by upregulation of Nlrc3 and Pirb and downregulation of Aim2, and S100b, which contrasts with the pro-inflammatory state observed in males.

Cardiovascular assessment confirmed elevated blood pressure in SHRs compared with Wistar rats, with male SHRs exhibiting a more pronounced vasomotor/neurohumoral autonomic profile than females, whereas females demonstrated a higher heart rate.

Transcriptomic profiling of the PVN revealed a greater number of differentially expressed genes in male SHRs, underscoring the impact of hypertension in males.

Consistent downregulation of Anxa1 and upregulation of Slc11a1 across both sexes highlights a potential shared mechanism of neuroinflammation in hypertensive states.

Key upregulated genes in male SHRs, including Bdnf and Agtr1a, may increases the baseline BP and enhance the VLF component of BP variability as a central feature of the male transcriptomic profile.

Compared with male SHRs, female SHRs exhibited an anti-inflammatory signature characterized by upregulation of Nlrc3 and Pirb and downregulation of Aim2, and S100b, which contrasts with the pro-inflammatory state observed in males.

The online version contains supplementary material available at 10.1186/s13293-026-00855-3.

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