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@ARTICLE{Mulder:868119,
      author       = {Mulder, Inge A. and Rubio-Beltran, Eloísa and Ibrahimi,
                      Khatera and Dzyubachyk, Oleh and Khmelinskii, Artem and
                      Hoehn, Mathias and Terwindt, Gisela M. and Wermer, Marieke
                      J. H. and MaassenVanDenBrink, Antoinette and van den
                      Maagdenberg, Arn M. J. M},
      title        = {{I}ncreased {M}ortality and {V}ascular {P}henotype in a
                      {K}nock-{I}n {M}ouse {M}odel of {R}etinal {V}asculopathy
                      {W}ith {C}erebral {L}eukoencephalopathy and {S}ystemic
                      {M}anifestations},
      journal      = {Stroke},
      volume       = {51},
      number       = {1},
      issn         = {1524-4628},
      address      = {Philadelphia, Pa.},
      publisher    = {Lippincott Williams $\&$ Wilkins},
      reportid     = {FZJ-2019-06706},
      pages        = {300-307},
      year         = {2020},
      abstract     = {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:
                      Emax: $37±8\%$ versus WT: Emax: $65±6\%,$ 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 mm3
                      versus WT: 52.9±5.6 mm3, 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.},
      cin          = {INM-3},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-3-20090406},
      pnm          = {572 - (Dys-)function and Plasticity (POF3-572)},
      pid          = {G:(DE-HGF)POF3-572},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31805844},
      UT           = {WOS:000504225600056},
      doi          = {10.1161/STROKEAHA.119.025176},
      url          = {https://juser.fz-juelich.de/record/868119},
}