Abstract
BACKGROUND: Neurovascular coupling (NVC) is essential for matching cerebral blood flow (CBF) to neuronal activity. While cortical NVC has been studied extensively, particularly in the context of sensory processing, little is known about NVC dynamics in deep brain regions, such as the hypothalamus, especially under disease conditions like heart failure (HF), where impaired cortical NVC has been linked to cognitive decline. Our goal in this study was to investigate salt-induced NVC responses in the hypothalamic supraoptic nucleus (SON) of rats with HF, and to determine the role of microglial purinergic signaling in modulating these responses. METHODS: Using in vivo two-photon imaging and real-time oxygen measurements in the SON, we assessed neurovascular responses to a systemic salt challenge in a well-established HF rat model that mimics clinical outcomes observed in the human population. Pharmacological and biosensor approaches were employed to dissect the contribution of key vasoactive mediators. RESULTS: Contrary to our original hypothesis, that HF would exacerbate salt-evoked inverse NVC (iNVC; vasoconstriction and hypoxia) as previously reported by our group in healthy rats, in HF, the NVC response was reversed. Here, salt-induced neuronal activation triggered vasodilation and increased SON pO₂, restoring oxygen levels to those of sham controls. This vasodilation was mediated by adenosine acting on A2A receptors and originated from a putative microglial source. Importantly, a masked, enhanced AVP-mediated vasoconstrictive component was still present, as revealed by biosensor assays, indicating a complex interplay between opposing vasoactive signals during HF. CONCLUSIONS: These findings reveal a previously unrecognized microglia-driven purinergic mechanism that overrides AVP-mediated vasoconstriction to restore SON oxygenation during salt challenges in HF. The polarity switch in hypothalamic NVC suggests a region- and disease-specific adaptation with potential relevance to neurohumoral dysregulation in HF.