# Role of Brain Pericyte KATP Channels in Physiological Hypoxia Sensing and Deficient Blood Flow Regulation

> **NIH NIH P20** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2024 · $358,415

## Abstract

The brain requires constant delivery of oxygen (O2) and nutrients through the bloodstream to maintain healthy 
neuronal function. Indeed, local or global dips in O2, called hypoxia, can precipitate central nervous system 
damage and neurodegeneration. Critically, clinical manifestations of chronic hypoxia/ischemia primarily occur 
in deep brain structures such as the subcortical white matter and thalamus. Indeed, deep brain 
hypoxia/ischemia is a putative mechanism in ischemic small vessel disease, which is prevalent and 
debilitating, accounting for over ~40% of all dementia cases and is by far the leading cause of vascular 
dementia. Of the entire brain vascular landscape, over 90% of all vessels are exceptionally small capillaries, 
consisting of end-to-end endothelial cell tubes with complete coverage by embedded perivascular cells called 
pericytes. We have recently demonstrated that the capillaries provide a massive sensing surface area within 
the brain and can transduce environmental stimuli (such as neuronal activity) into reliable and robust 
increases in blood flow. We have also demonstrated that capillaries possess the molecular machinery 
required to transduce extracellular adenosine, a key hypoxia-induced signaling molecule, into vasodilation 
and increased blood flow. Additionally, capillaries are a critical locus for dysfunction in small vessel disease 
pathology. The main objectives of this proposal are to examine the role deep brain capillaries play in 
hypoxia-induced blood flow responses and to determine whether deep brain hypoxia-sensing is disrupted in 
an animal model of cerebral small vessel disease. Therefore, I hypothesize that capillary adenosine 
sensing mediates deep-brain blood flow responses during hypoxia. I further hypothesize that hypoxia 
sensing is diminished in cerebral small vessel disease, leading to vascular dysfunction and hypoxic damage 
in deep brain structures. I will test these hypotheses with two distinct aims. First, I will elucidate the role 
adenosine signaling and KATP channel activity play in hypoxia-induced deep brain blood flow responses. 
Second, I will determine whether cSVD pathology disrupts hypoxia-induced blood flow responses and 
capillary-mediated electrical signaling. This project will provide significant physiological and pathological 
insights into blood delivery mechanisms within the deep brain. This proposal is conceptually and 
technically innovative due to the capillary-centric examination of hypoxia-sensing and the use of 
sophisticated deep brain imaging in well-characterized models of cerebral small vessel disease.

## Key facts

- **NIH application ID:** 11140140
- **Project number:** 5P20GM135007-05
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Nicholas Ryan Klug
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $358,415
- **Award type:** 5
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11140140

## Citation

> US National Institutes of Health, RePORTER application 11140140, Role of Brain Pericyte KATP Channels in Physiological Hypoxia Sensing and Deficient Blood Flow Regulation (5P20GM135007-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11140140. Licensed CC0.

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