Role of Purine-Converting Ecto-Enzymes in Angiogenic Phenotype of Pulmonary Artery Adventitial Vasa Vasorum Endothelial Cells of Chronically Hypoxic Calves - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 70

Chapter 5
Role of Purine-Converting Ecto-Enzymes
in Angiogenic Phenotype of Pulmonary Artery
Adventitial Vasa Vasorum Endothelial Cells
of Chronically Hypoxic Calves

Evgenia V. Gerasimovskaya, Kurt R. Stenmark, and Gennady G. Yegutkin

Abstract Our previous studies demonstrated that angiogenic expansion of the vasa
vasorum network can be observed in the pulmonary artery adventitia of chroni-
cally hypoxic calves. Because extracellular ATP and ADP are important regulators
of vascular cell function, we hypothesized that these nucleotides may contribute
to vasa vasorum neovascularization induced by chronic hypoxia. Treatment of pul-
monary artery adventitial vasa vasorum endothelial cells (VVEC) with exogenous
ATP or non-hydrolysable nucleotide analogs dramatically increased DNA synthesis
and migration. Similar mitogenic responses have been observed in lung microvas-
cular endothelial cells (MVEC), but not in endothelial cell isolated from large
blood vessels of the same animals, such as aorta (AOEC) and main pulmonary
artery (MPAEC). By using thin-layer chromatography assay, we also found that
cultured VVEC displayed substantially lower ecto-ADPase/NTPDase and ecto-5 -
nucleotidase activities compared to MPAEC and MVEC. In addition, VVEC are
characterized by higher activities of ATP-regenerating ecto-enzymes, adenylate
kinase and nucleotide diphosphokinase, consistent with a potent mitogenic effect of
exogenous nucleotides in VVEC versus MPA and MVEC. Together, these studies
indicate that VVEC, isolated from the sites of active neovascularization, may repre-
sent a unique pro-angiogenic phenotype with an augmented reliance to extracellular
ATP and ADP. Our studies also demonstrated important role of endothelial purine-
converting ecto-enzymes in the control of angiogenesis via directional regulation of
local nucleotide levels.

Keywords Angiogenesis · Vasa-vasorum · Vascular remodeling · Hypoxia ·

Pulmonary hypertension · Pulmonary circulation · Pulmonary artery ·

Aorta · Adventitia · Cell migration · Cell proliferation · Purinergic receptors ·

Intracellular signaling · Adenine nucleotides · Adenosine · ecto-NTPDase ·

ecto-5 -nucleotidase · Adenylate kinase · Nucleotide diphosphokinase

B E.V. Gerasimovskaya ( )

Department of Pediatrics Critical Care Medicine, University of Colorado Denver, Aurora,
CO 80045, USA
e-mail: [e-mail]