Circulating endothelial markers in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Nadine Pelzer, Roel Bijkerk, Marlies E.J. Reinders, Anton Jan Van Zonneveld, Michel D. Ferrari, Arn M.J.M. Van Den Maagdenberg, Jeroen Eikenboom, Gisela M. Terwindt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background and Purpose-Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease, caused by C-terminal truncating TREX1 mutations, that can be considered a model for stroke and vascular dementia. The pathophysiology of RVCL-S is largely unknown, but systemic endothelial involvement has been suggested, leading to pathology in the brain and other highly vascularized organs. Here, we investigated circulating endothelial markers to confirm endothelial involvement and identify biomarkers for disease activity. Methods-We measured circulating levels of von Willebrand factor (VWF) antigen, VWF propeptide, and angiopoietin-2 in members of 3 Dutch RVCL-S families and matched unrelated healthy controls. Stratified analyses based on symptomatology and age were performed. Results-We found elevated levels of VWF antigen, VWF propeptide, and angiopoietin-2 in TREX1 mutation carriers (n=31) compared with family members without a TREX1 mutation (n=33) and unrelated healthy controls (n=31; Kruskal-Wallis test P<0.001 for all comparisons). Effects were most pronounced in mutation carriers with clinical manifestations aged ≥40 years (Mann-Whitney U test P<0.001 for all comparisons). Compared with healthy controls, levels of VWF antigen (P=0.02) and angiopoietin-2 (P=0.04) were also elevated in mutation carriers aged <40 years. All 3 markers showed moderate correlations with markers of kidney and liver disease and inflammation (ie, systemic symptoms of RVCL-S). Conclusions-Our results confirm an important role of the endothelium in RVCL-S pathophysiology. VWF antigen, VWF propeptide, and angiopoietin-2 might serve as early biomarkers of disease activity. Our findings might also help to understand the pathophysiology of common neurovascular disorders, such as stroke.

Original languageEnglish
Pages (from-to)3301-3307
Number of pages7
JournalStroke
Volume48
Issue number12
DOIs
Publication statusPublished - 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants of the Netherlands Organization for Scientific Research (NWO; VIDI no. 91711319 to Dr Terwindt), the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NWO; CMSB no. 050-060-409 to Dr van den Maagdenberg), and the European Community (EC; FP7-EUROHEADPAIN no. 602633 to Drs van den Maagdenberg, Ferrari, and Terwindt and FP7-NIMBL no. 241779 to Dr van den Maagdenberg). They had no role in the design or conduct of the study.

Publisher Copyright:
© 2017 American Heart Association, Inc.

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