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Pericyte Microvesicles as Plasma Biomarkers Reflecting Brain Microvascular Signaling in Patients with Acute Ischemic Stroke

Gaceb, Abderahim LU ; Roupé, Linnea LU ; Enström, Andreas LU orcid ; Almasoudi, Wejdan LU ; Carlsson, Robert LU ; Lindgren, Arne G. LU and Paul, Gesine LU (2024) In Stroke 55(3). p.558-568
Abstract

BACKGROUND: Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important... (More)

BACKGROUND: Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important pathophysiological mechanisms. METHODS: Plasma samples were collected from patients with acute ischemic stroke (n=39) at 3 time points after stroke onset: 0 to 6 hours, 12 to 24 hours, and 2 to 6 days, and compared with controls (n=39). Pericyte-derived microvesicles were isolated based on cluster of differentiation 140b expression and quantified by flow cytometry. The protein content was evaluated using a proximity extension assay, and vascular signaling pathways were examined using molecular signature hallmarks and gene ontology. RESULTS: In this case-control study, patients with acute ischemic stroke showed significantly increased numbers of pericyte-derived microvesicles (median, stroke versus controls) at 12 to 24 hours (1554 versus 660 microvesicles/μL; P=0.0041) and 2 to 6 days after stroke (1346 versus 660 microvesicles/μL; P=0.0237). Their proteome revealed anti-inflammatory properties mediated via downregulation of Kirsten rat sarcoma virus and IL (interleukin)-6/JAK/STAT3 signaling at 0 to 6 hours, but proangiogenic as well as proinflammatory signals at 12 to 24 hours. Between 2 and 6 days, proteins were mainly associated with vascular remodeling as indicated by activation of Hedgehog signaling in addition to proangiogenic signals. CONCLUSIONS: We demonstrate that the plasma of patients with acute ischemic stroke reflects (1) an early and time-dependent increase of pericyte-derived microvesicles and (2) changes in the protein cargo of microvesicles over time indicating cell signaling specifically related to inflammation and vascular remodeling.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
microvesicles, pericytes, secretome, signaling, stroke
in
Stroke
volume
55
issue
3
pages
11 pages
publisher
American Heart Association
external identifiers
  • pmid:38323422
  • scopus:85186159653
ISSN
0039-2499
DOI
10.1161/STROKEAHA.123.045720
language
English
LU publication?
yes
id
07a2293d-903f-4e68-88ce-2c20e8d6a920
date added to LUP
2024-03-27 16:01:14
date last changed
2024-04-24 20:01:59
@article{07a2293d-903f-4e68-88ce-2c20e8d6a920,
  abstract     = {{<p>BACKGROUND: Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important pathophysiological mechanisms. METHODS: Plasma samples were collected from patients with acute ischemic stroke (n=39) at 3 time points after stroke onset: 0 to 6 hours, 12 to 24 hours, and 2 to 6 days, and compared with controls (n=39). Pericyte-derived microvesicles were isolated based on cluster of differentiation 140b expression and quantified by flow cytometry. The protein content was evaluated using a proximity extension assay, and vascular signaling pathways were examined using molecular signature hallmarks and gene ontology. RESULTS: In this case-control study, patients with acute ischemic stroke showed significantly increased numbers of pericyte-derived microvesicles (median, stroke versus controls) at 12 to 24 hours (1554 versus 660 microvesicles/μL; P=0.0041) and 2 to 6 days after stroke (1346 versus 660 microvesicles/μL; P=0.0237). Their proteome revealed anti-inflammatory properties mediated via downregulation of Kirsten rat sarcoma virus and IL (interleukin)-6/JAK/STAT3 signaling at 0 to 6 hours, but proangiogenic as well as proinflammatory signals at 12 to 24 hours. Between 2 and 6 days, proteins were mainly associated with vascular remodeling as indicated by activation of Hedgehog signaling in addition to proangiogenic signals. CONCLUSIONS: We demonstrate that the plasma of patients with acute ischemic stroke reflects (1) an early and time-dependent increase of pericyte-derived microvesicles and (2) changes in the protein cargo of microvesicles over time indicating cell signaling specifically related to inflammation and vascular remodeling.</p>}},
  author       = {{Gaceb, Abderahim and Roupé, Linnea and Enström, Andreas and Almasoudi, Wejdan and Carlsson, Robert and Lindgren, Arne G. and Paul, Gesine}},
  issn         = {{0039-2499}},
  keywords     = {{microvesicles; pericytes; secretome; signaling; stroke}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{558--568}},
  publisher    = {{American Heart Association}},
  series       = {{Stroke}},
  title        = {{Pericyte Microvesicles as Plasma Biomarkers Reflecting Brain Microvascular Signaling in Patients with Acute Ischemic Stroke}},
  url          = {{http://dx.doi.org/10.1161/STROKEAHA.123.045720}},
  doi          = {{10.1161/STROKEAHA.123.045720}},
  volume       = {{55}},
  year         = {{2024}},
}