Abstract
Blood is constantly in contact with a biological material, the blood vessel wall, without the need for anticoagulants to prevent clot formation on the vessel wall; however, manmade biomaterials require anticoagulants to prevent clot formation on the biomaterial. This study seeks to understand how some biomaterials elicit anticoagulant responses from endothelial cells (ECs), whereas others do not. Partial least squares regression analysis was used to correlate the activity of four relevant signaling molecules [extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), Akt, and IκB kinase (IKK)] with human umbilical vein EC secretion of prostacyclin and clotting time of whole blood in contact with these cells. Prostacyclin secretion was increased when JNK activity (mean of all time-points) was elevated and IKK activity at 30 min was reduced. In addition, the clotting time, R-time measured by thromboelastography, was increased (reduced coagulability) when activity of both ERK and JNK (mean of all time-points) were increased and when Akt activity was increased at longer contact times (24-72 h after cell contact with material). Inhibition of each signaling molecule with subsequent testing for prostacyclin secretion and R-time confirmed the interrelationship between EC intracellular signaling and prostacyclin secretion. Generally, JNK inhibition decreased and IKK inhibition increased prostacyclin secretion. Inhibition of ERK or JNK generally increased coagulability, and Akt inhibition decreased the R-time of samples normally eliciting reduced coagulability. These findings increase our understanding of the signaling pathways involved in endothelial prostacyclin release and suggest targets for developing EC-seeded biomaterial surfaces that can minimize coagulation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3374-3383 |
| Number of pages | 10 |
| Journal | Journal of Biomedical Materials Research - Part A |
| Volume | 100 A |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2012 |
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Keywords
- Biocompatible materials
- Extracellular matrix
- Intracellular signaling
- Systems biology
- Thrombosis
ASJC Scopus subject areas
- Biomedical Engineering
- Biomaterials
- Ceramics and Composites
- Metals and Alloys
Cite this
Intracellular signaling controls endothelial cell prostacyclin secretion and regulation of blood clotting time. / Shankarraman, Venkat; Davis-Gorman, Grace; McDonagh, Paul F.; Caplan, Michael.
In: Journal of Biomedical Materials Research - Part A, Vol. 100 A, No. 12, 12.2012, p. 3374-3383.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Intracellular signaling controls endothelial cell prostacyclin secretion and regulation of blood clotting time
AU - Shankarraman, Venkat
AU - Davis-Gorman, Grace
AU - McDonagh, Paul F.
AU - Caplan, Michael
PY - 2012/12
Y1 - 2012/12
N2 - Blood is constantly in contact with a biological material, the blood vessel wall, without the need for anticoagulants to prevent clot formation on the vessel wall; however, manmade biomaterials require anticoagulants to prevent clot formation on the biomaterial. This study seeks to understand how some biomaterials elicit anticoagulant responses from endothelial cells (ECs), whereas others do not. Partial least squares regression analysis was used to correlate the activity of four relevant signaling molecules [extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), Akt, and IκB kinase (IKK)] with human umbilical vein EC secretion of prostacyclin and clotting time of whole blood in contact with these cells. Prostacyclin secretion was increased when JNK activity (mean of all time-points) was elevated and IKK activity at 30 min was reduced. In addition, the clotting time, R-time measured by thromboelastography, was increased (reduced coagulability) when activity of both ERK and JNK (mean of all time-points) were increased and when Akt activity was increased at longer contact times (24-72 h after cell contact with material). Inhibition of each signaling molecule with subsequent testing for prostacyclin secretion and R-time confirmed the interrelationship between EC intracellular signaling and prostacyclin secretion. Generally, JNK inhibition decreased and IKK inhibition increased prostacyclin secretion. Inhibition of ERK or JNK generally increased coagulability, and Akt inhibition decreased the R-time of samples normally eliciting reduced coagulability. These findings increase our understanding of the signaling pathways involved in endothelial prostacyclin release and suggest targets for developing EC-seeded biomaterial surfaces that can minimize coagulation.
AB - Blood is constantly in contact with a biological material, the blood vessel wall, without the need for anticoagulants to prevent clot formation on the vessel wall; however, manmade biomaterials require anticoagulants to prevent clot formation on the biomaterial. This study seeks to understand how some biomaterials elicit anticoagulant responses from endothelial cells (ECs), whereas others do not. Partial least squares regression analysis was used to correlate the activity of four relevant signaling molecules [extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), Akt, and IκB kinase (IKK)] with human umbilical vein EC secretion of prostacyclin and clotting time of whole blood in contact with these cells. Prostacyclin secretion was increased when JNK activity (mean of all time-points) was elevated and IKK activity at 30 min was reduced. In addition, the clotting time, R-time measured by thromboelastography, was increased (reduced coagulability) when activity of both ERK and JNK (mean of all time-points) were increased and when Akt activity was increased at longer contact times (24-72 h after cell contact with material). Inhibition of each signaling molecule with subsequent testing for prostacyclin secretion and R-time confirmed the interrelationship between EC intracellular signaling and prostacyclin secretion. Generally, JNK inhibition decreased and IKK inhibition increased prostacyclin secretion. Inhibition of ERK or JNK generally increased coagulability, and Akt inhibition decreased the R-time of samples normally eliciting reduced coagulability. These findings increase our understanding of the signaling pathways involved in endothelial prostacyclin release and suggest targets for developing EC-seeded biomaterial surfaces that can minimize coagulation.
KW - Biocompatible materials
KW - Extracellular matrix
KW - Intracellular signaling
KW - Systems biology
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=84869095259&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84869095259&partnerID=8YFLogxK
U2 - 10.1002/jbm.a.34266
DO - 10.1002/jbm.a.34266
M3 - Article
C2 - 22767493
AN - SCOPUS:84869095259
VL - 100 A
SP - 3374
EP - 3383
JO - Journal of Biomedical Materials Research - Part B Applied Biomaterials
JF - Journal of Biomedical Materials Research - Part B Applied Biomaterials
SN - 0021-9304
IS - 12
ER -