Journal
STROKE
Volume 51, Issue 1, Pages 300-307Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.119.025176
Keywords
ischemic stroke; magnetic resonance imaging; vasculature
Categories
Funding
- Netherlands Organization for Scientific Research (NWO) [VIDI-91711349, VIDI-91717337, VIDI-91711319]
- Netherlands Brain Foundation [F2014(1)-22]
- Dutch Heart Foundation [2011T055, 2013-T083]
- International Retinal Research Foundation: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) 2019
- European Community Seventh Framework (FP7) [EUROHEADPAIN-602633, NIMBL-241779]
- European Community Marie Curie IndustryAcademia Partnerships and Pathways Program [BRAINPATH-612360]
- Dutch Technology Foundation STW [12721]
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Background and Purpose- Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an autosomal dominant small vessel disease caused by C-terminal frameshift mutations in the TREX1 gene that encodes the major mammalian 3 ' to 5 ' DNA exonuclease. RVCL-S is characterized by vasculopathy, especially in densely vascularized organs, progressive retinopathy, cerebral microvascular disease, white matter lesions, and migraine, but the underlying mechanisms are unknown. Methods- Homozygous transgenic RVCL-S knock-in mice expressing a truncated Trex1 (three prime repair exonuclease 1) protein (similar to what is seen in patients) and wild-type littermates, of various age groups, were subjected to (1) a survival analysis, (2) in vivo postocclusive reactive hyperemia and ex vivo Mulvany myograph studies to characterize the microvascular and macrovascular reactivity, and (3) experimental stroke after transient middle cerebral artery occlusion with neurological deficit assessment. Results- The mutant mice show increased mortality starting at midlife (P=0.03 with hazard ratio, 3.14 [95% CI, 1.05-9.39]). The mutants also show a vascular phenotype as evidenced by attenuated postocclusive reactive hyperemia responses (across all age groups; F[1, 65]=5.7, P=0.02) and lower acetylcholine-induced relaxations in aortae (in 20- to 24-month-old mice; RVCL-S knock-in: E-max: 37 +/- 8% versus WT: E-max: 65 +/- 6%, P=0.01). A vascular phenotype is also suggested by the increased infarct volume seen in 12- to 14-month-old mutant mice at 24 hours after infarct onset (RVCL-S knock-in: 75.4 +/- 2.7 mm(3) versus WT: 52.9 +/- 5.6 mm(3), P=0.01). Conclusions- Homozygous RVCL-S knock-in mice show increased mortality, signs of abnormal vascular function, and increased sensitivity to experimental stroke and can be instrumental to investigate the pathology seen in patients with RVCL-S.
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