Mechanistic exploration of phthalimide neovascular factor 1 using network analysis tools

Tissue Eng. 2007 Oct;13(10):2561-75. doi: 10.1089/ten.2007.0023.

Abstract

Neovascularization is essential for the survival and successful integration of most engineering tissues after implantation in vivo. The objective of this study was to elucidate possible mechanisms of phthalimide neovascular factor 1 (PNF1), a new synthetic small molecule proposed for therapeutic induction of angiogenesis. Complementary deoxyribonucleic acid microarray analysis was used to identify 568 transcripts in human microvascular endothelial cells (HMVECs) that were significantly regulated after 24-h stimulation with 30 muM of PNF1, previously known as SC-3-149. Network analysis tools were used to identify genetic networks of the global biological processes involved in PNF1 stimulation and to describe known molecular and cellular functions that the drug regulated most highly. Examination of the most significantly perturbed networks identified gene products associated with transforming growth factor-beta (TGF-beta), which has many known effects on angiogenesis, and related signal transduction pathways. These include molecules integral to the thrombospondin, plasminogen, fibroblast growth factor, epidermal growth factor, ephrin, Rho, and Ras signaling pathways that are essential to endothelial function. Moreover, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) of select genes showed significant increases in TGF-beta-associated receptors endoglin and beta glycan. These experiments provide important insight into the pro-angiogenic mechanism of PNF1, namely, TGF-beta-associated signaling pathways, and may ultimately offer new molecular targets for directed drug discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiogenic Proteins / metabolism*
  • Cells, Cultured
  • Drug Delivery Systems / methods
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology*
  • Gene Expression Profiling / methods*
  • Humans
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / genetics*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics*
  • Software

Substances

  • Angiogenic Proteins