Heparan sulfate proteoglycan, integrin, and syndecan-4 are mechanosensors mediating cyclic strain-modulated endothelial gene expression in mouse embryonic stem cell-derived endothelial cells.

It is widely believed that differentiation of embryonic stem cells (ESC) into viable endothelial cells (EC) for use in vascular tissue engineering can be enhanced by mechanical forces. In our previous work (Nikmanesh, Shi et al. 2012) we reported that shear stress enhanced important EC functional genes on a CD31+ /CD45- cell population derived from mouse ESC committed to the EC lineage. In the present study, in contrast to the effects of shear stress on this cell population, we observed that cyclic strain significantly reduced the expression of EC-specific marker genes (vWF, VE-cadherin, PECAM-1), tight junction protein genes (ZO-1, OCLD, CLD5), and vasoactive genes (eNOS, ET1), while it didn't alter the expression of COX-2. Taken together these studies indicate that only shear stress, not cyclic strain, is a useful mechanical stimulus for enhancing the properties of CD31+ /CD45- cells for use as EC in vascular tissue engineering. To begin to examine mechanisms controlling cyclic strain-induced suppression of gene expression in CD31+ /CD45- cells, we depleted the heparan sulfate (HS) component of the glycocalyx, blocked integrins and silenced the HS proteoglycan syndecan-4 in separate experiments. All of these treatments resulted in reversal of cyclic strain-induced gene suppression. The current study and our previous work (Nikmanesh, Shi et al. 2012) provide a deeper understanding of the mechanisms that balance the influence of cyclic strain and shear stress in endothelial cells. This article is protected by copyright. All rights reserved.