Protein z exerts pro-angiogenic effects and upregulates CXCR4.
Protein Z (PZ) is a vitamin K-dependent coagulation factor without catalytic activity. Evidence points towards PZ as an independent risk factor for the occurrence of human peripheral arterial disease. However, the role of PZ in ischemia-driven angiogenesis and vascular healing processes has not been...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4256373?pdf=render |
| _version_ | 1818142324771782656 |
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| author | Antje Butschkau Nana-Maria Wagner Berit Genz Brigitte Vollmar |
| author_facet | Antje Butschkau Nana-Maria Wagner Berit Genz Brigitte Vollmar |
| author_sort | Antje Butschkau |
| collection | DOAJ |
| description | Protein Z (PZ) is a vitamin K-dependent coagulation factor without catalytic activity. Evidence points towards PZ as an independent risk factor for the occurrence of human peripheral arterial disease. However, the role of PZ in ischemia-driven angiogenesis and vascular healing processes has not been elucidated so far.Angiogenic potency of PZ was assessed in established in vitro assays using endothelial cells. PZ-deficient (PZ(-/-)) mice and their wild-type littermates (PZ(+/+)) were subjected to hindlimb ischemia. Furthermore, PZ(-/-) mice were exposed to PZ expressing adenovirus (AdV-PZ) or control adenovirus (AdV-GFP). In an additional set of animals, PZ(-/-) mice were exposed to AdV-PZ and AdV-GFP, each in combination with the CXCR4 antagonist AMD3100.In vitro, PZ stimulated migratory activity and capillary-like tube formation of endothelial cells comparable to SDF-1. PZ(-/-) mice exhibited diminished hypoxia-driven neovascularization and reperfusion in post-ischemic hindlimbs, which was restored by adenoviral gene transfer up to levels seen in PZ(+/+) mice. The stimulatory impact of PZ on endothelial cells in vitro was abolished by siRNA targeting against PZ and PZ was not able to restore reduced migration after knock-down of CXCR4. The increased surface expression of CXCR4 on PZ-stimulated endothelial cells and the abrogated restoration of PZ(-/-) mice via AdV-PZ after concomitant treatment with the CXCR4 antagonist AMD3100 supports the idea that PZ mediates angiogenesis via a G-protein coupled pathway and involves the SDF-1/CXCR4 axis. This is underlined by the fact that addition of the G-protein inhibitor PTX to PZ-stimulated endothelial cells abolished the effect of PZ on capillary-like tube formation.The results of the current study reveal a role of PZ in ischemia-induced angiogenesis, which involves a G-protein coupled pathway and a raised surface expression of CXCR4. Our findings thereby extend the involvement of PZ from the coagulation cascade to a beneficial modulation of vascular homeostasis. |
| first_indexed | 2024-12-11T11:13:58Z |
| format | Article |
| id | doaj.art-c5daf277213a4ef8a9ef713d92036221 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T11:13:58Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c5daf277213a4ef8a9ef713d920362212022-12-22T01:09:24ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01912e11355410.1371/journal.pone.0113554Protein z exerts pro-angiogenic effects and upregulates CXCR4.Antje ButschkauNana-Maria WagnerBerit GenzBrigitte VollmarProtein Z (PZ) is a vitamin K-dependent coagulation factor without catalytic activity. Evidence points towards PZ as an independent risk factor for the occurrence of human peripheral arterial disease. However, the role of PZ in ischemia-driven angiogenesis and vascular healing processes has not been elucidated so far.Angiogenic potency of PZ was assessed in established in vitro assays using endothelial cells. PZ-deficient (PZ(-/-)) mice and their wild-type littermates (PZ(+/+)) were subjected to hindlimb ischemia. Furthermore, PZ(-/-) mice were exposed to PZ expressing adenovirus (AdV-PZ) or control adenovirus (AdV-GFP). In an additional set of animals, PZ(-/-) mice were exposed to AdV-PZ and AdV-GFP, each in combination with the CXCR4 antagonist AMD3100.In vitro, PZ stimulated migratory activity and capillary-like tube formation of endothelial cells comparable to SDF-1. PZ(-/-) mice exhibited diminished hypoxia-driven neovascularization and reperfusion in post-ischemic hindlimbs, which was restored by adenoviral gene transfer up to levels seen in PZ(+/+) mice. The stimulatory impact of PZ on endothelial cells in vitro was abolished by siRNA targeting against PZ and PZ was not able to restore reduced migration after knock-down of CXCR4. The increased surface expression of CXCR4 on PZ-stimulated endothelial cells and the abrogated restoration of PZ(-/-) mice via AdV-PZ after concomitant treatment with the CXCR4 antagonist AMD3100 supports the idea that PZ mediates angiogenesis via a G-protein coupled pathway and involves the SDF-1/CXCR4 axis. This is underlined by the fact that addition of the G-protein inhibitor PTX to PZ-stimulated endothelial cells abolished the effect of PZ on capillary-like tube formation.The results of the current study reveal a role of PZ in ischemia-induced angiogenesis, which involves a G-protein coupled pathway and a raised surface expression of CXCR4. Our findings thereby extend the involvement of PZ from the coagulation cascade to a beneficial modulation of vascular homeostasis.http://europepmc.org/articles/PMC4256373?pdf=render |
| spellingShingle | Antje Butschkau Nana-Maria Wagner Berit Genz Brigitte Vollmar Protein z exerts pro-angiogenic effects and upregulates CXCR4. PLoS ONE |
| title | Protein z exerts pro-angiogenic effects and upregulates CXCR4. |
| title_full | Protein z exerts pro-angiogenic effects and upregulates CXCR4. |
| title_fullStr | Protein z exerts pro-angiogenic effects and upregulates CXCR4. |
| title_full_unstemmed | Protein z exerts pro-angiogenic effects and upregulates CXCR4. |
| title_short | Protein z exerts pro-angiogenic effects and upregulates CXCR4. |
| title_sort | protein z exerts pro angiogenic effects and upregulates cxcr4 |
| url | http://europepmc.org/articles/PMC4256373?pdf=render |
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