EPAC1 promotes adaptive responses in human arterial endothelial cells subjected to low levels of laminar fluid shear stress: Implications in flow-related endothelial dysfunction

Cell Signal. 2016 Jun;28(6):606-19. doi: 10.1016/j.cellsig.2016.02.016. Epub 2016 Mar 14.

Abstract

Blood flow-associated fluid shear stress (FSS) dynamically regulates the endothelium's ability to control arterial structure and function. While arterial endothelial cells (AEC) subjected to high levels of laminar FSS express a phenotype resistant to vascular insults, those exposed to low levels of laminar FSS, or to the FSS associated with oscillatory blood flow, are less resilient. Despite numerous reports highlighting how the cAMP-signaling system controls proliferation, migration and permeability of human AECs (HAECs), its role in coordinating HAEC responses to FSS has received scant attention. Herein we show that the cAMP effector EPAC1 is required for HAECs to align and elongate in the direction of flow, and for the induction of several anti-atherogenic and anti-thrombotic genes associated with these events. Of potential therapeutic importance, EPAC1 is shown to play a dominant role the in response of HAECs to low levels of laminar FSS, such as would be found within atherosclerosis-prone areas of the vasculature. Moreover, we show that EPAC1 promotes these HAEC responses to flow by regulating Vascular Endothelial Growth Factor Receptor-2 and Akt activation, within a VE-cadherin (VECAD)/PECAM1-based mechanosensor. We submit that these findings are consistent with the novel proposition that promoting EPAC1-signaling represents a novel means through which to promote expression of an adaptive phenotype in HAECs exposed to non-adaptive FSS-encoded signals as a consequence of vascular disease.

Keywords: EPAC1; Fluid shear stress; Human arterial endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Arteries / cytology
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Gene Expression
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Mechanotransduction, Cellular*
  • Stress, Mechanical

Substances

  • Guanine Nucleotide Exchange Factors
  • RAPGEF3 protein, human