Short-term stress preconditioning activates sympathetic innervation in the testes to mitigate testicular ischemia-reperfusion injury.

Abstract

Testicular tissues are highly vulnerable to oxidative stress and external insults due to their unique physiological microenvironment; thus, developing protective interventions is critical. We reveal that preconditioning through short-term stress-induced sympathetic nervous system (SNS) activation effectively mitigates testicular ischemia-reperfusion injury (IRI) in mice. Pre-activation of the SNS via diverse stressors markedly reduced seminiferous tubular damage and oxidative biomarkers compared to untreated controls. Mechanistically, the protective effect is mediated by dopamine-beta hydroxylase-expressing neurons in the rostral ventrolateral medulla (DBH^RVLM), which enhance sympathetic innervation in the testes. Optogenetic and chemogenetic approaches confirmed that DBH^RVLM neuron activation elevates testicular norepinephrine levels and attenuates tissue damage. Furthermore, we identify testicular macrophages as one of key mediators of this protection, demonstrating their immunomodulatory response to sympathetic signaling. These results support the "good stress" hypothesis, underscoring the beneficial effects of acute stress. Since the short-term stress response is a conserved adaptive mechanism in mammals, our findings suggest that SNS-mediated preconditioning could extend beyond testicular protection, potentially offering therapeutic insights for other oxidative stress-sensitive organs.