Polarity Switch (<i>from vasoconstriction to vasodilation)</i>of Salt-Induced Neurovascular Coupling Responses in the Hypothalamus of Rats with Heart Failure

Neurovascular coupling (NVC), the process that links neuronal activity to cerebral blood flow changes, has been mainly studied in superficial brain areas, namely the neocortex. Still, whether the conventional, rapid and spatially restricted NVC response can be generalized to deeper, and functionally diverse brain regions, and whether this is altered in disease states, remains unknown. We addressed this important gap in our knowledge by implementing a novel in vivo, real-time two-photon experimental approach using a transgenic eGFP VP rat. In a recent study, we demonstrated that a systemic salt load evoked a significant intraparenchymal arteriole vasoconstriction mediated by locally released VP within the SON. The salt-induced vasoconstriction resulted in a progressive decrease in SON pO2 and increased expression of the hypoxia-inducible factor (HIF)-1α mRNA. In this study, we aimed to investigate whether the salt-evoked neurovascular response was affected in rats with chronic heart failure (HF). We found that under baseline conditions, SON pO2 levels were lower in HF compared to sham rats (p&lt;0.01, n=7, paired t test). Basal vascular diameter of the internal carotid artery (ICA) and intraparenchymal arterioles were not significantly different between sham and HF rats (for ICA; p=.1147, n=6, unpaired t test, and for intraparenchymal arterioles; p=.8815, n=6, paired t test). Despite this initial basal hypoxia, we found that the salt challenge induced intraparenchymal arteriolar vasodilatation (one-way RM ANOVA; p = 0.011; n = 6) and a progressive increase in SON pO2 (one-way RM ANOVA; p &lt; 0.001; n = 6) in HF rats. Direct application of VP in the SON via a microdialysis probe still induced arteriolar vasoconstriction (p&lt;0.01, n=5, paired t test). We tested then the hypothesis that the salt-evoked vasodilation in HF rats is mediated by local release of adenosine. In fact, we found that intra SON delivery of an adenosine A2 receptor agonist (CGS21680) in control rats causes vasodilation of intraparenchymal arterioles (one-way RM ANOVA; p &lt; 0.01; n = 4). Finally, we found that the salt-evoked vasodilation in HF rats was absent when an adenosine A2A receptor antagonist (ZM241385) was locally delivered into the SON. In fact, salt-dependent vasoconstriction was unmasked under this condition (one-way RM ANOVA; p &lt; 0.001; n = 4), which was significantly higher compared to the salt-induced vasoconstriction in Sham rats (p&lt;0.01, n=6 in sham and n=4 in HF, unpaired t-test). Taken together, our results support a change in the polarity of the salt-induced NVC in HF rats, from vasoconstriction (VP-mediated) to vasodilation (adenosine-mediated). The cellular source of adenosine, as well as the overall functional significance of the NVC switch during HF remains to be determined. 1R01HL162575-01 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.