Home › Research › Vascular contributions
Proteins Involved in Endothelial Function and Inflammation Are Implicated in Cerebral Small Vessel Disease
Zihan Sun, Eric L. Harshfield, Frank‐Erik de Leeuw, Stephen Burgess, Adam S. Butterworth, Niels P. Riksen, Ziad Mallat, Hugh Stephen Markus. Stroke, 2025-01-17
Topic: Brain proteins, microglia and lab models
). Moreover, 12 proteins related to endothelial function and inflammation were associated with neuroimaging features of SVD. Cross-sectional analyses showed 5 of the 13 proteins (EPHA2 [ephrin type-A receptor 2], METAP1D [methionine aminopeptidase 1D, mitochondrial], FLT4 [vascular endothelial growth factor receptor 3], COL2A1, and TIMD4 [T-cell immunoglobulin and mucin domain-containing protein 4]) were associated with cognitive performance with effects concordant with their MR findings. Survival analyses with the Fine-Gray models indicated that 5 of the 13 proteins (EPHA2, METAP1D, FLT4, APOE [apolipoprotein E], and PDE5A [cGMP-specific 3',5'-cyclic phosphodiesterase]) were associated with the risk of all-cause dementia or stroke independent of age and sex, consistent with their MR evidence. Our findings suggest that endothelial-platelet activation and complement-mediated regulation of inflammation play roles in SVD and identify potential therapeutic targets and pathways.
Key findings
- Moreover, 12 proteins related to endothelial function and inflammation were associated with neuroimaging features of SVD.
- Cross-sectional analyses showed 5 of the 13 proteins (EPHA2 [ephrin type-A receptor 2], METAP1D [methionine aminopeptidase 1D, mitochondrial], FLT4 [vascular endothelial growth factor receptor 3], COL2A1, and TIMD4 [T-cell immunoglobulin and mucin domain-containing protein 4]) were associated with cognitive performance with effects concordant with their MR findings.
- Survival analyses with the Fine-Gray models indicated that 5 of the 13 proteins (EPHA2, METAP1D, FLT4, APOE [apolipoprotein E], and PDE5A [cGMP-specific 3',5'-cyclic phosphodiesterase]) were associated with the risk of all-cause dementia or stroke independent of age and sex, consistent with their MR evidence.
- Our findings suggest that endothelial-platelet activation and complement-mediated regulation of inflammation play roles in SVD and identify potential therapeutic targets and pathways.
Why it matters
This study found that 12 proteins related to endothelial function and inflammation were associated with neuroimaging features of small vessel disease, and 5 of 13 proteins were linked to risk of all-cause dementia or stroke. The findings suggest potential therapeutic targets and pathways, but no treatment was tested in this cross-sectional analysis.
Study details
- Study designcross-sectional
- Participants35
- Evidence strengthModerate
How this study scored 57/100
Published in a peer-reviewed journal, and it is a snapshot of people at one point in time. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Stroke) |
| Journal's citation record | 3 / 4 | Stroke: journal h-index 455 (OpenAlex, 2026-10-29) |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 | 1 / 4 | 35 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 14 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 7.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 14 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Hugh Stephen Markus: h-index 137 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Inserm: institution h-index 1,988 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39818967) |
| Free to read | 2 / 2 | Free to read |
| Total | 57 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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 8 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
Sun, Z., Harshfield, E. L., de Leeuw, F., Burgess, S., Butterworth, A. S., Riksen, N. P., et al. (2025). Proteins Involved in Endothelial Function and Inflammation Are Implicated in Cerebral Small Vessel Disease. Stroke. https://doi.org/10.1161/strokeaha.124.049079
Vancouver
Sun Z, Harshfield EL, de Leeuw F, Burgess S, Butterworth AS, Riksen NP, et al. Proteins Involved in Endothelial Function and Inflammation Are Implicated in Cerebral Small Vessel Disease. Stroke. 2025. doi:10.1161/strokeaha.124.049079. PMID: 39818967.
BibTeX
@article{sun2025-39818967,
author = {Sun, Zihan and Harshfield, Eric L. and de Leeuw, Frank‐Erik and Burgess, Stephen and Butterworth, Adam S. and Riksen, Niels P. and Mallat, Ziad and Markus, Hugh Stephen},
title = {{Proteins Involved in Endothelial Function and Inflammation Are Implicated in Cerebral Small Vessel Disease}},
journal = {Stroke},
year = {2025},
doi = {10.1161/strokeaha.124.049079},
pmid = {39818967},
url = {https://doi.org/10.1161/strokeaha.124.049079}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
1 study in the alzhub library lists this one in its references.