Ectonucleotidases of CD39 Family Modulate Vascular Inflammation and Thrombosis in Transplantation

Simon C. Robson; Yan Wu; Xiaofeng Sun; Christoph Knosalla; Karen Dwyer; Keiichi Enjyoji

doi:10.1055/s-2005-869527

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2005; 31(2): 217-233
DOI: 10.1055/s-2005-869527

Ectonucleotidases of CD39 Family Modulate Vascular Inflammation and Thrombosis in Transplantation

Simon C. Robson¹ ^, ² , Yan Wu² , Xiaofeng Sun² , Christoph Knosalla³ , Karen Dwyer² , Keiichi Enjyoji²

¹Associate Professor, Vascular Biology and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
²Vascular Biology and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
³Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Abstract

ABSTRACT

Transplantation results in exposure of the graft vasculature to warm and cold ischemia, followed by perfusion by circulating blood constituents and obligatory oxidant stress. Further graft injury occurs as consequences of acute humoral cellular rejection or chronic transplant vasculopathy, or both. Extracellular nucleotide stimulation of purinergic type 2 (P2) receptors are key components of platelet, endothelial cell (EC), and leukocyte activation resulting in vascular thrombosis and inflammation in vivo. CD39, the prototype nucleoside triphosphate diphosphohydrolase (NTPDase-1) is highly expressed on endothelium; in contrast, CD39L1/NTPDase-2 (a preferential adenosine triphosphatase [ATPase]) is found on vascular adventitial cells. Both ectoenzymes influence thrombogenesis by the regulated hydrolysis of extracellular nucleotides that differentially regulate P2-receptor activity and function in platelets and vascular cells. The intracytoplasmic domains of NTPDase-1 may also independently influence cellular activation and proliferation. NTPDase activity is substantively lost in the vasculature of injured or rejected grafts. A role for NTPDase-1 in thromboregulation has been validated by generation of mutant mice either null for cd39 or overexpressing human CD39. Administration of soluble NTPDase or induction of CD39 by adenoviral vectors, or both, are also of benefit in several models of transplantation. Administration of soluble CD39 or targeted expression may have future therapeutic application in transplantation-associated and other vascular diseases.

KEYWORDS

Antibodies - CD39 - endothelial cell - kidney - NTPDase - platelets - transplantation - vasculature

Full Text

References

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