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PKCδ regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes

Jamison, J and Wang, JHC and Wells, A (2014) PKCδ regulates force signaling during VEGF/CXCL4 induced dissociation of endothelial tubes. PLoS ONE, 9 (4).

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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-δ/myosin light chain-2 (PKCδ/MLC-2) signaling axis becomes a candidate mechanism to drive endothelial dissociation. We hypothesize that PKCδ 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 PKCδ inhibition. During combined CXCL4+VEGF treatment, increased contractility mediated by MLC-2 that is dependent on PKCδ regulation. As cellular force is transmitted to focal adhesions, zyxin, a focal adhesion protein that is mechano-responsive, was upregulated after PKCδ inhibition. This study suggests that growth factor regulation of PKCδ may be involved in CXCL4-mediated dissociation of endothelial cords. © 2014 Jamison et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Jamison, J
Wang, JHCwanghc@pitt.eduWANGHC
Wells, Aahw6@pitt.eduAHW6
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHotchin, Neil A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > McGowan Institute for Regenerative Medicine
Date: 3 April 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0093968
Schools and Programs: School of Medicine > Orthopaedic Surgery
School of Medicine > Pathology
Refereed: Yes
Date Deposited: 30 Jun 2014 15:48
Last Modified: 13 Oct 2017 22:59
URI: http://d-scholarship.pitt.edu/id/eprint/21967

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