Loading...
The Role of Cerebral Adenosine Sensing Across the Artery-Capillary Continuum
Hand, Lillian Sarah
Hand, Lillian Sarah
Citations
Altmetric:
License
DOI
Abstract
The brain, a major consumer of oxygen and nutrients, is perfused by an extensive vascular network that tightly regulates cerebral blood flow (CBF). Episodes of hypoxia are rapidly corrected in healthy conditions by CBF increase, with failure to do so contributing to pathology like cerebral small vessel disease (cSVD). The mechanisms linking hypoxia to vascular responses, and their breakdown in disease, is unclear. Hypoxia substantially elevates brain adenosine levels, which has a well-documented dilatory effect on large surface brain vessels. However, most of the brain vasculature is made up of small parenchymal arterioles and capillaries (> 95%), where the effects of hypoxia and adenosine are unknown. This project investigated the mechanisms of hypoxia-induced vasodilation and adenosine signaling in the cerebral vasculature. Dilation of isolated pial arteries to adenosine was investigated in the presence of U46619, a thromboxane A2 (TXA2) receptor agonist, and paxilline, a large conductance voltage- and Ca2+-activated K+ channel (BKCa) blocker, with no notable dilation under either condition. The response to hypoxia in pial vessels and penetrating arterioles was characterized using two-photon microscopy, with the penetrating arterioles demonstrating a significantly greater dilation to hypoxia. The presence of adenosine A2A receptor antagonist ZM 241385 modestly impaired hypoxia-induced dilation. These findings suggest that hypoxia-induced adenosine signaling differs between vascular zones, with penetrating arterioles displaying greater sensitivity than pial arteries, and that BKCa channels may not be a downstream target of physiological adenosine signaling. This work offers important insight into CBF regulation and lays groundwork for future investigations of the microvasculature.
Description
Date
2025-01-01