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Pericyte K ATP Channel Hyperactivity Contributes to Layer IV Cortex Hypoperfusion in Cerebral Small Vessel Disease
Danielle A Jeffrey, Hannah R Ferris, Niloufar Khakpour, Colin H. Peters, Catherine Proenza, Nikolaos M. Tsoukias, Fabrice Dabertrand. Physiology, 2025-05-01
Topic: Brain proteins, microglia and lab models
Our research, conducted both in vivo and ex vivo, demonstrated a 50% decrease in pressure-induced constriction in the CADASIL ACT zone. Membrane potential recordings indicated that CADASIL ACT zone pericytes were notably more hyperpolarized (-51 mV) than control pericytes (-32 mV). Our ex vivo pressure myography and in vivo cranial window experiments revealed that the CADASIL ACT zone minimally responded to K ATP agonist pinacidil, whereas controls exhibited significant dilation (17% versus 44%). Conversely, the CADASIL ACT zone exhibited a robust constriction in response to K ATP antagonist glibenclamide, unlike controls (28% versus 10%). Further investigation into K ATP channel hyperactivity in CADASIL using intact microvascular perforated patch revealed that ACT zone pericytes had a significantly higher basal current, which was sensitive to the K ATP antagonist glibenclamide. In silico modeling using membrane potential, patch-clamp, and ex vivo pressure myography data suggested that K ATP channel hyperactivity increases blood flow in the upper cortical layers at the expense of layer IV, leading to significant hypoperfusion in that region. These results support the novel concept that CADASIL’s impact on arteriolar reactivity further extends to the capillary level and ACT zone pericytes. K ATP channel hyperactivity contributes to impaired cortical blood flow distribution across different layers, enhancing perfusion in the upper layers while reducing it in layer IV. Overall, these results add valuable contributions to our understanding of SVDs and introduce new targets that could aid in rescuing the cerebral blood flow dysregulation and devastating pathological remodeling seen in CADASIL patients. This research was funded by NHLBI: DAJ F31HL170645, FD R01HL136636, NINDS: FD RF1/R01NS129022, R01/RF1NS140137 and cureCADASIL. 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.
Key findings
- Our research, conducted both in vivo and ex vivo, demonstrated a 50% decrease in pressure-induced constriction in the CADASIL ACT zone.
- Membrane potential recordings indicated that CADASIL ACT zone pericytes were notably more hyperpolarized (-51 mV) than control pericytes (-32 mV).
- Our ex vivo pressure myography and in vivo cranial window experiments revealed that the CADASIL ACT zone minimally responded to K ATP agonist pinacidil, whereas controls exhibited significant dilation (17% versus 44%).
- Conversely, the CADASIL ACT zone exhibited a robust constriction in response to K ATP antagonist glibenclamide, unlike controls (28% versus 10%).
- Further investigation into K ATP channel hyperactivity in CADASIL using intact microvascular perforated patch revealed that ACT zone pericytes had a significantly higher basal current, which was sensitive to the K ATP antagonist glibenclamide.
Why it matters
In tissue and animal experiments on CADASIL, a hereditary small vessel disease, pericytes in the affected zone showed KATP channel hyperactivity that modeling suggested reduces blood flow to layer IV of the cortex. This identifies a possible mechanism and target at the capillary level, but it is early laboratory work and does not show any treatment for Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 31/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Physiology) |
| Journal's citation record | 2 / 4 | Physiology: journal h-index 168 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 1 / 6 | Cited 0.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Fabrice Dabertrand: h-index 21 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Colorado Anschutz: institution h-index 768 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 31 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Jeffrey, D. A., Ferris, H. R., Khakpour, N., Peters, C. H., Proenza, C., Tsoukias, N. M., et al. (2025). Pericyte K ATP Channel Hyperactivity Contributes to Layer IV Cortex Hypoperfusion in Cerebral Small Vessel Disease. Physiology. https://doi.org/10.1152/physiol.2025.40.s1.1626
Vancouver
Jeffrey DA, Ferris HR, Khakpour N, Peters CH, Proenza C, Tsoukias NM, et al. Pericyte K ATP Channel Hyperactivity Contributes to Layer IV Cortex Hypoperfusion in Cerebral Small Vessel Disease. Physiology. 2025. doi:10.1152/physiol.2025.40.s1.1626.
BibTeX
@article{jeffrey2025-f8f4ff1d,
author = {Jeffrey, Danielle A and Ferris, Hannah R and Khakpour, Niloufar and Peters, Colin H. and Proenza, Catherine and Tsoukias, Nikolaos M. and Dabertrand, Fabrice},
title = {{Pericyte K ATP Channel Hyperactivity Contributes to Layer IV Cortex Hypoperfusion in Cerebral Small Vessel Disease}},
journal = {Physiology},
year = {2025},
doi = {10.1152/physiol.2025.40.s1.1626},
url = {https://doi.org/10.1152/physiol.2025.40.s1.1626}
}
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