4.7 Article

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

Journal

DIABETES
Volume 65, Issue 7, Pages 1916-1928

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db15-1450

Keywords

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Funding

  1. Canadian Institutes of Health Research (CIHR) [GSD-121812]
  2. Banting and Best Diabetes Centre
  3. Natural Sciences and Engineering Research Council of Canada
  4. Heart and Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research
  5. Ontario Graduate Scholarship
  6. CIHR [DHY-121263, FRN-119345]
  7. Peterborough K.M. Hunter Foundation
  8. NSERC CREATE MATCH
  9. Russian Science Foundation [14-50-00060]
  10. Canada Foundation for Innovation and Ontario Research Fund [RI -11810]
  11. Heart and Stroke Foundation of Ontario (HSFO) [G13-0002813]
  12. HSFO [NIA-6581, CIA-7432]
  13. University of Toronto
  14. Russian Science Foundation [14-50-00060] Funding Source: Russian Science Foundation

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Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation.

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