PKC? regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes.

ABSTRACT: Wound healing requires the vasculature to re-establish itself from the severed ends; endothelial cells within capillaries must detach from neighboring cells before they can migrate into the nascent wound bed to initiate angiogenesis. The dissociation of these endothelial capillaries is driven partially by platelets' release of growth factors and cytokines, particularly the chemokine CXCL4/platelet factor-4 (PF4) that increases cell-cell de-adherence. As this retraction is partly mediated by increased transcellular contractility, the protein kinase c-?/myosin light chain-2 (PKC?/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKC? activation induces contractility through MLC-2 to promote dissociation of endothelial cords after exposure to platelet-released CXCL4 and VEGF. To investigate this mechanism of contractility, endothelial cells were allowed to form cords following CXCL4 addition to perpetuate cord dissociation. In this study, CXCL4-induced dissociation was reduced by a VEGFR inhibitor (sunitinib malate) and/or PKC? inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKC? regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKC? inhibition. This study suggests that growth factor regulation of PKC? may be involved in CXCL4-mediated dissociation of endothelial cords.

SUBMITTER: Jamison J 

PROVIDER: S-EPMC3974837 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature