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

Edyta Węgłowska,Daria Kamińska,Bartłomiej Grobelski,Dariusz Pawełczak,Stanisław Bielecki,Marek Kołodziejczyk,Edyta Gendaszewska-Darmach,Maria Koziołkiewicz

doi:10.3390/ijms23010238

Edyta Węgłowska, Daria Kamińska + Show 6 more

Open Access

https://doi.org/10.3390/ijms23010238

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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.

Highlights

Transmembrane G protein-coupled receptors (GPCRs) constitute a diverse and broad superfamily of proteins
Within GPCRs, significant academic and industry effort has been put into developing agonist and antagonist ligands for the P2Y receptors that respond to extracellular nucleotides
RT-qPCR analyzes of P2Y genes were performed for human umbilical vein endothelial cells (HUVECs) and human primary fibroblasts isolated from adult skin (HDF) due to their crucial role in the angiogenesis process

Summary

Introduction

Transmembrane G protein-coupled receptors (GPCRs) constitute a diverse and broad superfamily of proteins. Within GPCRs, significant academic and industry effort has been put into developing agonist and antagonist ligands for the P2Y receptors that respond to extracellular nucleotides. ATP is an agonist for P2Y2 and P2Y11 receptors; ADP activates P2Y1, P2Y12, and P2Y13. UTP recognizes P2Y2 and P2Y4 while UDP is a ligand for the P2Y6 receptor, and a nucleotide sugar conjugate (UDP-glucose) is an agonist for the P2Y14. Based on their sequence similarity, the P2Y receptors have been grouped into two subfamilies, namely

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