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Critical role of telomerase in regulating cerebral vascular function and redox environment
Author(s) -
AitAissa Karima,
Hockenberry Joseph,
Gutterman David D,
Geurts Aron,
Beyer Andreas M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.953.5
Subject(s) - vasodilation , oxidative stress , endothelial dysfunction , medicine , enos , telomerase , nitric oxide , cerebral arteries , endocrinology , nitric oxide synthase , chemistry , biochemistry , gene
Rationale Cerebrovascular dysfunction has been directly been linked to cerebral micro bleeds and cognitive decline in clinical settings and rodent models of stroke and dementias. Recent clinical studies suggest that oxidative stress may facilitate the development and progression of impaired Flow‐mediated dilation (FMD) in patients with cerebrovascular disease. FMD is the most physiological relevant form of endothelial‐mediated vasodilation. Our laboratory has previously shown that telomerase, a ribo‐nucleoprotein that counteracts telomere shortening, has a protective effect on endothelial function under conditions of oxidative stress in the human microcirculation. For example, in the presence of coronary artery disease, decreased telomerase activity contributes to a shift in the mediator of FMD from atheroprotective nitric oxide (NO) to pro‐inflammatory and atherogenic hydrogen peroxide (H 2 O 2 ). Endothelial dysfunction in the cerebral vasculature has been directly linked to cerebral microbleeds and cognitive decline in models of stroke and dementia, thus we hypothesized that TERT plays a critical role in maintaining normal NO‐mediated vasodilation in the cerebral vasculature. Methods Using Crisp/Cas9 we generated a novel deletion model for TERT (the catalytic subunit of telomerase) in rats on the WKY background. Middle cerebral arteries (MCA) were isolated from wild type (WT) and TERT −/− rats, prepared for videomicroscopy, and FMD was measured. The mediator of FMD was determined using a pharmacological inhibitor of NO synthase (L‐NAME) and a scavenger of H 2 O 2 (PEG‐catalase). Results No changes in the magnitude of FMD were observed in MCA from TERT −/− compared to WT rats (max dilation: TERT −/− 71.97±14.7% vs. WT 80.9±10.6%; n≥3). In WT animals, pre‐incubation with L‐NAME abolished FMD while PEG‐catalase had no effect on FMD (max dilation: L‐NAME −5.8±7%*; Peg‐catalase 76.6±8.6%; n≥3; p<0.05). Conversely, in TERT −/− animals FMD was not affected in the presence of L‐NAME but abolished in presence of Peg‐catalase (max dilation: L‐NAME 57.8.0±16.5%; Peg‐catalase −4.3±2.4*%; n≥3; p>0.05 two way ANOVA RM). Conclusions Telomerase deficiency causes a switch in the vasoactive mediator of FMD from NO to H 2 O 2 , creating a pro‐oxidative environment in the cerebral vasculature. Understanding the regulatory role of telomerase in mediating this mechanistic switch may provide a novel therapeutic strategy for the treatment or prevention of cerebrovascular dysfunction. Support or Funding Information R01 HL113612/R21 OD018306