| First Author | Bowley SR | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Pages | 14151 | PubMed ID | 28218242 |
| Mgi Jnum | J:244264 | Mgi Id | MGI:5913043 |
| Doi | 10.1038/ncomms14151 | Citation | Bowley SR, et al. (2017) Protein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation. Nat Commun 8:14151 |
| abstractText | Protein disulfide isomerase (PDI), secreted by platelets and endothelial cells on vascular injury, is required for thrombus formation. Using PDI variants that form mixed disulfide complexes with their substrates, we identify by kinetic trapping multiple substrate proteins, including vitronectin. Plasma vitronectin does not bind to alphavbeta3 or alphaIIbbeta3 integrins on endothelial cells and platelets. The released PDI reduces disulfide bonds on plasma vitronectin, enabling vitronectin to bind to alphaVbeta3 and alphaIIbbeta3. In vivo studies of thrombus generation in mice demonstrate that vitronectin rapidly accumulates on the endothelium and the platelet thrombus following injury. This process requires PDI activity and promotes platelet accumulation and fibrin generation. We hypothesize that under physiologic conditions in the absence of secreted PDI, thrombus formation is suppressed and maintains a quiescent, patent vasculature. The release of PDI during vascular injury may serve as a regulatory switch that allows activation of proteins, among them vitronectin, critical for thrombus formation. |
