Extracellular Nucleotides Affect the Proangiogenic Behavior of Fibroblasts, Keratinocytes, and Endothelial Cells

Int J Mol Sci. 2021 Dec 27;23(1):238. doi: 10.3390/ijms23010238.

Abstract

Chronic wound healing is currently a severe problem due to its incidence and associated complications. Intensive research is underway on substances that retain their biological activity in the wound microenvironment and stimulate the formation of new blood vessels critical for tissue regeneration. This group includes synthetic compounds with proangiogenic activity. Previously, we identified phosphorothioate analogs of nucleoside 5'-O-monophosphates as multifunctional ligands of P2Y6 and P2Y14 receptors. The effects of a series of unmodified and phosphorothioate nucleotide analogs on the secretion of VEGF from keratinocytes and fibroblasts, as well as their influence on the viability and proliferation of keratinocytes, fibroblasts, and endothelial cells were analyzed. In addition, the expression profiles of genes encoding nucleotide receptors in tested cell models were also investigated. In this study, we defined thymidine 5'-O-monophosphorothioate (TMPS) as a positive regulator of angiogenesis. Preliminary analyses confirmed the proangiogenic potency of TMPS in vivo.

Keywords: angiogenesis; extracellular nucleotides; phosphorothioate analogs; purinergic receptors.

MeSH terms

  • Adult
  • Cell Proliferation / drug effects
  • Extracellular Space / chemistry*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / physiology*
  • Gene Expression Regulation / drug effects
  • HaCaT Cells
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / physiology*
  • Neovascularization, Physiologic* / drug effects
  • Neovascularization, Physiologic* / genetics
  • Nucleotides / pharmacology*
  • Phosphorothioate Oligonucleotides / pharmacology
  • Receptors, Purinergic P2Y / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Nucleotides
  • Phosphorothioate Oligonucleotides
  • Receptors, Purinergic P2Y
  • Vascular Endothelial Growth Factor A