Chronic sleep fragmentation induces endothelial dysfunction and structural vascular changes in mice

Sleep. 2014 Nov 1;37(11):1817-24. doi: 10.5665/sleep.4178.


Study objectives: Sleep fragmentation (SF) is a common occurrence and constitutes a major characteristic of obstructive sleep apnea (OSA). SF has been implicated in multiple OSA-related morbidities, but it is unclear whether SF underlies any of the cardiovascular morbidities of OSA. We hypothesized that long-term SF exposures may lead to endothelial dysfunction and altered vessel wall structure.

Methods and results: Adult male C57BL/6J mice were fed normal chow and exposed to daylight SF or control sleep (CTL) for 20 weeks. Telemetric blood pressure and endothelial function were assessed weekly using a modified laser-Doppler hyperemic test. Atherosclerotic plaques, elastic fiber disruption, lumen area, wall thickness, foam cells, and macrophage recruitment, as well as expression of senescence-associated markers were examined in excised aortas. Increased latencies to reach baseline perfusion levels during the post-occlusive period emerged in SF mice with increased systemic BP values starting at 8 weeks of SF and persisting thereafter. No obvious atherosclerotic plaques emerged, but marked elastic fiber disruption and fiber disorganization were apparent in SF-exposed mice, along with increases in the number of foam cells and macrophages in the aorta wall. Senescence markers showed reduced TERT and cyclin A and increased p16INK4a expression, with higher IL-6 plasma levels in SF-exposed mice.

Conclusions: Long-term sleep fragmentation induces vascular endothelial dysfunction and mild blood pressure increases. Sleep fragmentation also leads to morphologic vessel changes characterized by elastic fiber disruption and disorganization, increased recruitment of inflammatory cells, and altered expression of senescence markers, thereby supporting a role for sleep fragmentation in the cardiovascular morbidity of OSA.

Keywords: atherosclerosis; cell senescence; endothelial function; sleep apnea.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / immunology
  • Aorta / pathology
  • Biomarkers / blood
  • Blood Pressure
  • Cellular Senescence
  • Chemokine CXCL1 / blood
  • Eating
  • Elastic Tissue / pathology
  • Endothelium, Vascular / pathology*
  • Endothelium, Vascular / physiopathology*
  • Heart Rate
  • Insulin-Like Growth Factor Binding Protein 3 / blood
  • Interleukin-6 / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Plaque, Atherosclerotic / pathology
  • Sleep Apnea, Obstructive / blood
  • Sleep Apnea, Obstructive / complications*
  • Sleep Apnea, Obstructive / pathology
  • Sleep Apnea, Obstructive / physiopathology
  • Sleep Deprivation / blood
  • Sleep Deprivation / complications
  • Sleep Deprivation / pathology*
  • Sleep Deprivation / physiopathology*


  • Biomarkers
  • Chemokine CXCL1
  • Insulin-Like Growth Factor Binding Protein 3
  • Interleukin-6