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Thromb Haemost 2005; 93(04): 735-742
DOI: 10.1160/TH04-09-0576
Endothelium and Vascular Development
Schattauer GmbH

Modulation of endothelial cell migration by extracellular nucleotides

Involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways
Elzbieta Kaczmarek
1   Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
,
Laurie Erb
2   University of Missouri-Columbia, Columbia, Missouri, USA
,
Katarzyna Koziak
1   Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
3   Warsaw Medical University, Warsaw, Poland
,
Robert Jarzyna
1   Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
,
Marcia R. Wink
1   Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
,
Olaf Guckelberger
1   Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
,
Krzysztof J. Blusztajn
4   Boston University School of Medicine, Boston, Massachusetts, USA
,
Vickery Trinkaus-Randall
4   Boston University School of Medicine, Boston, Massachusetts, USA
,
Gary A. Weisman
2   University of Missouri-Columbia, Columbia, Missouri, USA
,
Simon C. Robson
1   Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
› Author AffiliationsGrant support: This project was supported by grants: HL66167 (EK), KBN3P05A08723 and Polpharma- Foundation (KK), AG09525 (JKB), NEI EY06000 (VTR), AG18357 (GAW), and HL57307/HL63972 (SCR).
Further Information

Publication History

Received 08 September 2004

Accepted after resubmission 21 January 2005

Publication Date:
14 December 2017 (online)

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Summary

Extracellular nucleotides bind to type-2 purinergic/pyrimidinergic (P2) receptors that mediate various responses, such as cell activation, proliferation and apoptosis, implicated in inflammatory processes. The role of P2 receptors and their associated signal transduction pathways in endothelial cell responses has not been fully investigated. Here, it is shown that stimulation of human umbilical vein endothelial cells (HUVEC) with extracellular ATP or UTP increased intracellular free calcium ion concentrations ([Ca2+]i), induced phosphorylation of focal adhesion kinase (FAK), p130cas and paxillin, and caused cytoskeletal rearrangements with consequent cell migration. Furthermore, UTP increased migration of HUVEC in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. BAPTA or thapsigargin inhibited the extracellular nucleotide-induced increase in [Ca2+]i, a response crucial for both FAK phosphorylation and cell migration. Furthermore, long-term exposure of HUVEC to ATP and UTP, agonists of the G protein-coupled P2Y2 and P2Y4 receptor subtypes, caused upregulation of αv integrin expression, a cell adhesion molecule known to directly interact with P2Y2 receptors. Our results suggest that extracellular nucleotides modulate signaling pathways in HUVEC influencing cell functions, such as cytoskeletal changes, cellular adhesion and motility, typically associated with integrin-activation and the action of growth factors. We propose that P2Y2 and possibly P2Y4 receptors mediate those responses that are important in vascular inflammation, atherosclerosis and angiogenesis.

Keywords

Endothelial cells - extracellular nucleotides - migration - P2 receptors - FAK
 

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