A1 Journal article – refereed

Endothelial cells cope with hypoxia-induced depletion of ATP via activation of cellular purine turnover and phosphotransfer networks

List of Authors: Karolina Losenkova, Mariachiara Zuccarini, Mikko Helenius, Guillaume Jacquemet, Evgenia Gerasimovskaya, Camilla Tallgren, Sirpa Jalkanen, Gennady G. Yegutkin

Publisher: Elsevier B.V.

Publication year: 2018

Journal: BBA - Molecular Basis of Disease

Journal name in source: Biochimica et Biophysica Acta - Molecular Basis of Disease

Volume number: 1864

Issue number: 5

Number of pages: 12

eISBN: 1879-260X

ISSN: 0925-4439

eISSN: 1879-260X

DOI: http://dx.doi.org/10.1016/j.bbadis.2018.03.001


Intravascular ATP and adenosine have emerged as important regulators of endothelial barrier function, vascular remodeling and neovascularization at various pathological states, including hypoxia, inflammation and oxidative stress. By using human umbilical vein endothelial cells (HUVEC) and bovine vasa vasorum endothelial cells (VVEC) as representatives of macro- and microvessel phenotypes, this study was undertaken to evaluate cellular mechanisms contributing to physiological adaptation of vascular endothelium to hypoxia, with a particular emphasis on ectoenzymatic purine-converting activities and their link to intracellular ATP homeostasis and signaling pathways. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), ecto-5′-nucleotidase/CD73 and ecto-adenylate kinase activities were determined by thin-layer chromatography (TLC) with 3H-labellednucleotide substrates. Exposure of HUVEC and VVEC to 1% O2 for 4–24 h triggered rather moderateactivation of ATP breakdown into adenosine via the CD39-CD73 axis. Additional TLC analysis of salvage pathways revealed the enhanced ability of hypoxic HUVEC to convert cell-incorporated [3H]adenosine into [3H]ADP/ATP. Furthermore, following a period of hypoxia, HUVEC underwent concurrent changes in intracellular signaling manifested in the depletion of putative ATP stores and targeted up-regulation of phosphop53, p70S6K/mTOR and other tyrosine kinases. The revealed complex implication of both extrinsic and intrinsic mechanisms into a tuned hypoxia-induced control of purine homeostasis and signaling may open up further research for the development of pharmacological treatments to improve endothelial cell function under diseaseconditions associated with a loss of cellular ATP during oxygen deprivation.

Last updated on 2021-24-06 at 11:15