Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta

Int J Mol Sci. 2022 Jun 24;23(13):7012. doi: 10.3390/ijms23137012.

Abstract

Intermittent hypoxia (IH), the major feature of obstructive sleep apnea syndrome (OSAS), induces atherosclerosis and elastic fiber alterations. VE-cadherin cleavage is increased in OSAS patients and in an IH-cellular model. It is mediated by HIF-1 and Src-tyr-kinases pathways and results in endothelial hyperpermeability. Our aim was to determine whether blocking VE-cadherin cleavage in vivo could be an efficient strategy to inhibit deleterious IH-induced vascular remodeling, elastic fiber defects and atherogenesis. VE-cadherin regulation, aortic remodeling and atherosclerosis were studied in IH-exposed C57Bl/6J or ApoE-/-mice treated or not with Src-tyr-kinases inhibitors (Saracatinib/Pazopanib) or a HIF-1 inhibitor (Acriflavine). Human aortic endothelial cells were exposed to IH and treated with the same inhibitors. LDL and the monocytes transendothelium passage were measured. In vitro, IH increased transendothelium LDL and monocytes passage, and the tested inhibitors prevented these effects. In mice, IH decreased VE-cadherin expression and increased plasmatic sVE level, intima-media thickness, elastic fiber alterations and atherosclerosis, while the inhibitors prevented these in vivo effects. In vivo inhibition of HIF-1 and Src tyr kinase pathways were associated with the prevention of IH-induced elastic fiber/lamella degradation and atherogenesis, which suggests that VE-cadherin could be an important target to limit atherogenesis and progression of arterial stiffness in OSAS.

Keywords: VE-cadherin; atherosclerosis; elastic fiber fragmentation; endothelial dysfunction; intermittent hypoxia; obstructive sleep apnea syndrome.

MeSH terms

  • Animals
  • Antigens, CD
  • Aorta / metabolism
  • Atherosclerosis* / metabolism
  • Cadherins
  • Carotid Intima-Media Thickness
  • Elastic Tissue / metabolism
  • Endothelial Cells / metabolism
  • Hypoxia / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Sleep Apnea, Obstructive* / metabolism

Substances

  • Antigens, CD
  • Cadherins
  • cadherin 5