Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo
Abstract
Activated protein C (APC), a natural anticoagulant, has recently been demonstrated to activate the mitogen-activated protein kinase (MAPK) pathway in endothelial cells in vitro. Because the MAPK pathway is implicated in endothelial cell proliferation, it is possible that APC induces endothelial cell proliferation, thereby causing angiogenesis. We examined this possibility in the present study. APC activated the MAPK pathway, increased DNA synthesis, and induced proliferation in cultured human umbilical vein endothelial cells dependent on its serine protease activity. Antibody against the endothelial protein C receptor (EPCR) inhibited these events. Early activation of the MAPK pathway was inhibited by an antibody against protease-activated receptor-1, whereas neither late and complete activation of the MAPK pathway nor endothelial cell proliferation were inhibited by this antibody. APC activated endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinase–dependent phosphorylation, followed by activation of protein kinase G, suggesting that APC bound to EPCR might activate the endothelial MAPK pathway by a mechanism similar to that of VEGF. APC induced morphogenetic changes resembling tube-like structures of endothelial cells, whereas DIP-APC did not. When applied topically to the mouse cornea, APC clearly induced angiogenesis in wild-type mice, but not in eNOS knockout mice. These in vitro events induced by APC might at least partly explain the angiogenic activity in vivo. This angiogenic activity of APC might contribute to maintain proper microcirculation in addition to its antithrombotic activity.
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Activated protein C enhances neurovascular interplay by stimulating endothelial proliferation and tube formation and inducing proliferation and migration of neural precursor cells via PAR1.
“The serine protease activated protein C enhances this neurovascular interplay, stimulating endothelial proliferation and tube formation60 and inducing proliferation and migration of neural precursor cells61 via protease-activated receptor 1.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [60]
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- Authors
- Uchiba, M., Okajima, K., Oike, Y., Ito, Y., Fukudome, K., Isobe, H., & Suda, T.
- Affiliations
- Saga University (JP)
- Venue
- Circulation Research
- Published
- 2004-07-09
- Volume
- 95
- Issue
- 1
- Pages
- 34-41
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2105823536
- Cited by
- 162
- References
- 31
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 5 · 2020: 5 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 8
- FWCI
- 8.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- activated protein C, endothelial cell proliferation, angiogenesis, MAPK signaling, endothelial protein C receptor, protease-activated receptor 1, endothelial nitric oxide synthase, phosphatidylinositol 3-kinase, protein kinase G, serine protease activity, human umbilical vein endothelial cells, corneal neovascularization, microcirculation, antithrombotic activity
- MeSH terms
- Animals, Antibodies, Blood Coagulation Factors, Cells, Cultured, DNA, Endothelium, Vascular, Enzyme Activation, Cyclic GMP, Humans, Nitric Oxide, Protein C, Receptors, Cell Surface, Neovascularization, Physiologic, MAP Kinase Signaling System, Endothelial Cells, Receptor, PAR-1, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Mice
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