Heart failure‐induced reprogramming of salt‐evoked neurovascular coupling in the rat hypothalamus

Abstract Neurovascular coupling (NVC) is essential for matching cerebral blood flow to neuronal activity. While NVC has been extensively studied in the cerebral cortex, far less is known about its regulation in deep brain regions such as the hypothalamus, particularly under pathological conditions. Heart failure (HF) is associated with impaired cortical NVC and cognitive dysfunction, but its impact on hypothalamic NVC remains unclear. Here, we investigated salt‐evoked NVC in the hypothalamic supraoptic nucleus (SON) of rats with HF. In vivo two‐photon imaging combined with real‐time tissue oxygen measurements was used to assess parenchymal arteriole diameter and local in the SON during a systemic hypertonic saline challenge in a rat model of HF. Pharmacological interventions and biosensor approaches were employed to dissect the contributions of key vasoactive signalling pathways. Under baseline conditions, HF rats exhibited reduced SON compared with sham animals. Unexpectedly, salt loading in HF rats elicited a vasodilatory NVC response accompanied by a progressive increase in SON , restoring oxygen levels toward those observed in sham rats. This polarity shift was mediated by adenosine signalling through A 2A receptors and depended on intact vasopressin (AVP) signalling. Notably, blockade of A 2A receptors unmasked an underlying AVP‐dependent vasoconstriction, indicating the coexistence of competing vasoactive mechanisms during salt challenge. These findings demonstrate a state‐dependent reorganization of hypothalamic NVC in HF, in which adenosine‐dependent vasodilatation predominates over AVP‐mediated vasoconstriction during salt loading. This adaptive shift highlights the dynamic regulation of neurovascular signalling in the hypothalamus and may have broader implications for neurohumoral control in cardiovascular disease. image Key points Neurovascular coupling (NVC) is well characterized in the cerebral cortex but remains poorly understood in the hypothalamic nuclei regulating homeostatic and neurohumoral functions. Heart failure (HF) is associated with a basal hypoperfused and hypoxic state of the hypothalamic supraoptic nucleus (SON), indicating impaired local neurovascular regulation at rest. During systemic salt loading, NVC in the SON of HF rats undergoes a polarity switch, with vasodilatation and improved tissue oxygenation replacing the vasoconstrictive response in sham animals. This state‐dependent reorganization involves adenosine signalling via A 2A receptors and is functionally dependent on intact vasopressin/V 1A receptor signalling, indicating that opposing vasoactive pathways jointly shape the net vascular response to salt loading in HF. These findings highlight dynamic, region‐specific regulation of hypothalamic neurovascular signalling in cardiovascular disease, with implications for neurohumoral control during homeostatic challenge.