Perturbed mechanotransduction by endothelial surface glycocalyx modification greatly impairs the arteriogenic process

Daniel R. Potter, Jurgen van Teeffelen, Hans Vink, Bernard M. van den Berg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

Abstract

The mechanisms that trigger initiation of arteriogenesis in response to pathogenic obstruction of arterial flow are not fully understood. Our objective is to determine whether glycocalyx mediated mechanotransduction of fluid shear stress to the endothelial layer is an essential first step in inducing arteriogenesis. Mice were implanted with an osmotic minipump containing saline or hyaluronan synthase inhibitor 4-methylesculetin (4ME) 2 wk before femoral artery ligation. 4ME was effective in modifying the endothelial glycocalyx as measured by dextran exclusion and perfused boundary region changes. Glycocalyx modification resulted in a 52% (P = 0.002) reduction in perfusion restoration through the 21-day follow-up [area under the curve, 4.9 +/- 1.1 (n = 11) vs. 10.2 +/- 3.2 (n = 10), 4ME vs. control (Ctrl)]. Upon femoral artery ligation, no change in collateral vessel diameter in 4ME treated mice (49.8 +/- 26.3 vs. 47.1 +/- 14.0 mu m, ligated vs unligated) was observed (Ctrl, 88.5 +/- 18.8 vs. 35.1 +/- 3.0 mu m, ligated vs unligated, P <0.05). This impaired arteriogenic process was accompanied by lack of local induction of both endothelial and smooth muscle cell activation (Ki67, endothelial nitric oxide synthase, and ICAM-1), as well as a failure to recruit CD11b-positive cells in 4ME-treated collateral vessels (0.012 +/- 0.003 vs. 0.010 +/- 0.003 cells/mu m vessel perimeter, ligated vs. unligated), whereas in Ctrls, the number of CD11b cells was increased (0.024 +/- 0.002 vs. 0.010 +/- 0.004 cells/mu m vessel perimeter, P <0.05). Modification of the glycocalyx by inhibition of hyaluronan synthesis renders the endothelium unresponsive to altered hemodynamic conditions resulting from femoral artery ligation, which results in a hampered restoration of distal perfusion.
Original languageEnglish
Pages (from-to)H711-H717
JournalAmerican Journal of Physiology-heart and Circulatory Physiology
Volume309
Issue number4
DOIs
Publication statusPublished - 15 Aug 2015

Keywords

  • mechanotransduction
  • endothelial glycocalyx
  • hyaluronan
  • arteriogenesis

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