Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo

Mitsuhiro Uchiba, Kenji Okajima, Yuichi Oike, Yasuhiro Ito, Kenji Fukudome, Hirotaka Isobe, Toshio Suda

Research output: Contribution to journalArticle

118 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)34-41
Number of pages8
JournalCirculation Research
Volume95
Issue number1
DOIs
Publication statusPublished - 2004 Jul 9

Fingerprint

Protein C
Mitogen-Activated Protein Kinases
Endothelial Cells
Cell Proliferation
Nitric Oxide Synthase Type III
In Vitro Techniques
Antibodies
Phosphatidylinositol 3-Kinase
PAR-1 Receptor
Cyclic GMP-Dependent Protein Kinases
Human Umbilical Vein Endothelial Cells
Serine Proteases
Microcirculation
Knockout Mice
Cornea
Anticoagulants
Vascular Endothelial Growth Factor A
Phosphorylation

Keywords

  • Activated protein C
  • Angiogenesis
  • Endothelial protein C receptor
  • Mitogen-activated protein kinase
  • Protease-activated receptor-1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. / Uchiba, Mitsuhiro; Okajima, Kenji; Oike, Yuichi; Ito, Yasuhiro; Fukudome, Kenji; Isobe, Hirotaka; Suda, Toshio.

In: Circulation Research, Vol. 95, No. 1, 09.07.2004, p. 34-41.

Research output: Contribution to journalArticle

Uchiba, Mitsuhiro ; Okajima, Kenji ; Oike, Yuichi ; Ito, Yasuhiro ; Fukudome, Kenji ; Isobe, Hirotaka ; Suda, Toshio. / Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. In: Circulation Research. 2004 ; Vol. 95, No. 1. pp. 34-41.
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