Date of Completion

2025

Document Type

Honors College Thesis

Department

Neuroscience

Thesis Type

Honors College, College of Arts and Science Honors

First Advisor

Dr. Nicholas Klug

Second Advisor

Dr. Molly Stanley

Third Advisor

Dr. Yangguang Ou

Keywords

hypoxia, cerebral blood flow, adenosine, penetrating arterioles, pial arteries, capillaries

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.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Available for download on Friday, May 01, 2026

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