Protein Z-deficiency is associated with enhanced neointima formation and inflammatory response after vascular injury in mice

Int J Clin Exp Pathol. 2014 Aug 15;7(9):6064-71. eCollection 2014.


Background: 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 atherosclerotic vascular diseases. The aim of this study was to investigate the role of PZ in vascular arterial disease.

Material and methods: PZ-deficient (PZ(-/-)) mice and their wild-type littermates (PZ(+/+)) were subjected to unilateral carotid artery injury by using ferric chloride and dissected 21 days thereafter for histological analysis. Human aortic smooth muscle cells (SMC) were used for in vitro wound healing assay to assess the influence of PZ on SMC migration and for cell proliferation studies.

Results: Morphometric analysis of neointima formation revealed a significantly increased area and thickness of the neointima and subsequently increased luminal stenosis in carotid arteries of PZ(-/-) mice compared to PZ(+/+) mice (p < 0.05, n = 9). Immunohistochemical analysis of neointima lesion composition revealed significantly higher numbers of PCNA-positive and α-SMA-positive cells in the neointima of PZ(-/-) mice. Furthermore, PZ showed an anti-migratory potency in in vitro wound healing assay with SMCs, while no effect of PZ on SMC proliferation was detectable. Conclusion: PZ contributes to a reduced neointima formation after vascular injury, underlining the modulatory role of the coagulation cascade in vascular homeostasis.

Keywords: Atherosclerosis; coagulation; critical leg ischemia; smooth muscle cells; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Blood Proteins / deficiency*
  • Blood Proteins / genetics
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Carotid Artery Injuries / chemically induced
  • Carotid Artery Injuries / genetics
  • Carotid Artery Injuries / metabolism*
  • Carotid Artery Injuries / pathology
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Chlorides
  • Disease Models, Animal
  • Ferric Compounds
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / injuries
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Neointima*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Time Factors
  • Vascular System Injuries / chemically induced
  • Vascular System Injuries / genetics
  • Vascular System Injuries / metabolism*
  • Vascular System Injuries / pathology


  • Acta2 protein, mouse
  • Actins
  • Blood Proteins
  • Chlorides
  • Ferric Compounds
  • Proliferating Cell Nuclear Antigen
  • plasma protein Z
  • ferric chloride