Sickle red blood cell-derived extracellular vesicles activate endothelial cells and enhance sickle red cell adhesion mediated by von Willebrand factor

Ran An, Yuncheng Man, Kevin Cheng, Tianyi Zhang, Chunsheng Chen, Fang Wang, Fuad Abdulla, Erdem Kucukal, William J. Wulftange, Utku Goreke, Allison Bode, Lalitha V. Nayak, Gregory M. Vercellotti, John D. Belcher, Jane A. Little, Umut A. Gurkan

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Endothelial activation and sickle red blood cell (RBC) adhesion are central to the pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV-mediated short-term non-transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2 h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin- or SS REV-induced microvascular stasis in SS mice with implanted dorsal skin-fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target.

Original languageEnglish (US)
Pages (from-to)552-563
Number of pages12
JournalBritish journal of haematology
Volume201
Issue number3
DOIs
StatePublished - May 2023

Bibliographical note

Funding Information:
This work is supported by National Heart, Lung, and Blood Institute (NHLBI) R01HL133574 (Gurkan), OT2HL152643 (Gurkan), R01HL114567 (Vercellotti/Belcher), K25HL159358 (An), and T32HL134622 (An). This article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Funding Information:
This work is supported by National Heart, Lung, and Blood Institute (NHLBI) R01HL133574 (Gurkan), OT2HL152643 (Gurkan), R01HL114567 (Vercellotti/Belcher), K25HL159358 (An), and T32HL134622 (An). This article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Ran An, Jane A. Little, Umut A. Gurkan and Case Western Reserve University have financial interests in Hemex Health Inc. Jane A. Little, Erdem Kucukal, Umut A. Gurkan and Case Western Reserve University have financial interests in BioChip Labs Inc. Umut A. Gurkan and Case Western Reserve University have financial interests in Xatek Inc. Umut A. Gurkan has financial interests in DxNow Inc. Financial interests include licensed intellectual property, stock ownership, research funding, employment, and consulting. Hemex Health Inc. offers point‐of‐care diagnostics for haemoglobin disorders, anaemia, and malaria. BioChip Labs Inc. offers commercial clinical microfluidic biomarker assays for inherited or acquired blood disorders. Xatek Inc. offers point‐of‐care global assays to evaluate the haemostatic process. DxNow Inc. offers microfluidic and bio‐imaging technologies for in vitro fertilisation, forensics and diagnostics. Competing interests of Case Western Reserve University employees are overseen and managed by the Conflict of Interests Committee according to a Conflict‐of‐Interest Management Plan. Gregory M. Vercellotti and John D. Belcher receive research funding from Omeros, CSL Behring, Hilhurst Biopharmaceuticals and Astellas/Mitobridge. JDB is a consultant for Astellas/Mitobridge. GMV is a consultant for Sanofi and Astellas/Mitobridge.

Publisher Copyright:
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Keywords

  • adamts 13
  • endothelial inflammation
  • extracellular vesicles
  • sickle cell disease
  • von willebrand factor

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