Chronic Social Stress Drives Hypertension and Anxiety in Mice via Autonomic Dysfunction

Social adversity — including discrimination and low socioeconomic status — is strongly linked to elevated rates of obesity, hypertension, and cardiovascular disease in humans. Yet the direct psychosocial stress component, independent of confounders like poor diet, is underappreciated mechanistically. This study used chronic social defeat stress (CSDS) in adult male C57BL/6J mice to dissect how repeated social subordination translates into measurable cardiometabolic and behavioral pathology.

The CSDS paradigm involved brief (≤10 min) daily defeat sessions conducted by dominant CD-1 resident mice, followed by sensory cohabitation behind a perforated divider for approximately 14 days. A total of 35 control and 32 CSDS mice were studied, with subsets receiving radiotelemetry implants, body composition scans, behavioral testing, plasma assays, and adrenal RNA sequencing.

Body mass increased in CSDS mice, driven by gains in both lean and fluid mass rather than fat alone. Multiple somatic indices of chronic stress were elevated. Behaviorally, CSDS mice spent significantly more time in the closed arms of the elevated plus maze and made fewer entries into the center zone of the open field, indicating robust anxiety-like behavior without differences in overall locomotion.

Cardiovascular telemetry provided the study's most striking findings. Early defeat sessions produced acute blood pressure spikes accompanied by increased activity and temperature — a normal stress response. During the first few days, blood pressure returned to baseline by the light cycle. However, after 14 days of CSDS, blood pressure elevations became sustained throughout the light phase, while activity and core body temperature paradoxically decreased. This dissociation suggests a progressive shift toward neurogenic hypertension rather than simple arousal-driven pressure increases.

Heart rate variability (HRV) analysis using time-domain methods and spontaneous baroreflex analysis using HemoLab software both showed significant reductions in CSDS mice compared to controls. Decreased HRV and baroreflex gain indicate impaired parasympathetic tone and diminished cardiovascular reflex control — hallmarks of autonomic dysfunction associated with hypertension risk in humans. Adrenal transcriptome analysis (bulk RNA-seq, n=6/group) revealed gene expression changes consistent with altered HPA axis signaling and sympathoadrenal activity, providing a molecular correlate for the observed physiological changes.

Collectively, these data establish CSDS as a translationally relevant mouse model for stress-induced hypertension, capturing the progression from acute reactivity to chronic sustained elevation, accompanied by autonomic impairment and anxiety. The model opens pathways to investigate neural, endocrine, and inflammatory mechanisms linking social adversity to cardiometabolic disease — a critical priority given worsening health disparities in human populations.