Abstract

We investigated the use of bone-marrow derived endothelial progenitor cells (EPCs) for the treatment of microvascular endothelial injury caused by inflammatory diseases. As activation of the monomeric RhoGTPase Cdc42 signals annealing of adherens junctions (AJs) in the endothelial barrier, we examined the possibility that EPCs could restore endothelial barrier dysfunction by promoting Cdc42 activation in endothelial cells (ECs). We observed that co-culture of EPCs with ECs prevented the decrease in transendothelial electrical resistance (TER), a measure of AJ assembly, and the decrease in VE-cadherin expression induced by thrombin (4 U/mL). EPCs also significantly reduced the formation of inter-endothelial gaps mediated by RhoA activation as well as myosin light chain phosphorylation in response to thrombin. We showed that EPCs induced activation of Cdc42 in ECs and increased TER within 15 min after the addition EPCs to ECs, indicating the enhancement of endothelial barrier function. Addition of EPCs after thrombin-induced disruption of AJs also promoted rapid recovery of TER compared to controls. Based on siRNA knockdown data, the endothelial barrier protective effect of EPCs was mediated by Cdc42 activation in ECs. Thus, EPC-mediated activation of Cdc42 in ECs decreases basal endothelial permeability and prevents endothelial hyper-permeability induced by the mediator thrombin. EPC/EC cross-talk is a critical mechanism regulating endothelial barrier function suggesting the value of EPCs in the treatment of microvascular injury associated with vascular inflammation.

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