PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design

Eur Heart J. 2014 Mar;35(12):808-20. doi: 10.1093/eurheartj/eht496. Epub 2013 Dec 11.


Background: Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury.

Methods and results: PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the β-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NFkB. Furthermore, inhibition of PI3K/p110α with PIK75 or a specific siRNA selectively impaired proliferation and migration of VSMC while sparing EC completely. Treatment with PIK75 did not induce endothelial senescence nor inhibit endothelium-dependent relaxations. In line with this observation, treatment with PIK75 selectively inhibited neointima formation without affecting re-endothelialization following vascular injury.

Conclusion: Following vascular injury, PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization. Hence, PI3K/p110α represents an attractive new target in DES design.

Keywords: Endothelium; PI3K/p110α; Re-endothelialization; Restenosis; Thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Drug-Eluting Stents*
  • Endothelium, Vascular / enzymology
  • GTP Phosphohydrolases / metabolism
  • Hydrazones / pharmacology
  • Immunosuppressive Agents / pharmacology
  • Leukocytes, Mononuclear / enzymology
  • Male
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / drug effects
  • NF-kappaB-Inducing Kinase
  • Neointima / enzymology
  • Nitric Oxide / biosynthesis
  • Paclitaxel / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Sirolimus / pharmacology
  • Sulfonamides / pharmacology
  • Thrombosis / enzymology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Hydrazones
  • Immunosuppressive Agents
  • PIK 75
  • Phosphoinositide-3 Kinase Inhibitors
  • Plasminogen Activator Inhibitor 1
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Protein Serine-Threonine Kinases
  • GTP Phosphohydrolases
  • Paclitaxel
  • Sirolimus