Transcriptomic Profiling of the Hypothalamic PVN Reveals Sexually Dimorphic Pathways of Sympathoexcitation and Neuroinflammation in a Rat Model of Hypertension

Introduction: 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 regulation by modulating sympathetic tone and releasing neuropeptides that affect the function of the cardiovascular system. 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 blood pressure. Methods: To accomplish this goal, we sequenced RNA from the PVNs of normotensive Wistar rats (WR) and Spontaneously Hypertensive Rats (SHR), both male and female. We also measured cardiovascular parameters and analyzed their variability. Results: Cardiovascular analyses revealed greater blood pressure (BP) in SHRs than in Wistar rats andgreater participation of the sympathetic tone in SHR males than in their female counterparts. The impact of hypertension was also evident in the gene expression analyses, which revealed influences from both the hypertensive state and sex. Compared with female SHRs, male SHRs presented a marked increase in differentially expressed genes (DEGs), highlighting the greater impact of hypertension on the PVN transcriptome in males. Key upregulated genes in males, including Brain-Derived Neurotrophic Factor ( Bdnf ), Hypocretin ( Hcrt ), and Angiotensin II Receptor Type 1 ( Agtr1a ), are associated with elevated sympathetic tone. In contrast, the female transcriptomic signature was characterized by the upregulation of anti-inflammatory pathways, with significant upregulation of NLR Family CARD Domain Containing 3 ( Nlrc3 ) and downregulation of Absent in Melanoma 2 ( Aim2 ). Notably, several genes, such as Annexin A1 ( Anxa1 ), whose downregulation is associated with neuroinflammation, were consistently downregulated in both sexes. Conclusion: These results provide new insights into the cardiovascular and molecular basis of sex differences in hypertension, suggesting a greater contribution of sympathetic tone in males, whereas in females a greater anti-inflammatory component. These findings offer a valuable framework for developing future sex-specific therapeutic strategies.