© 2000 American Heart Association, Inc.
Cellular Biology |
Tie2 Receptor Expression Is Stimulated by Hypoxia and Proinflammatory Cytokines in Human Endothelial Cells
From the Departments of Nephrology and Medical Intensive Care (C.W., J.S.J., U.F., K.-U.E.), Neonatology (P.K.), Physiology (K.D.W.), and Anatomy (S.B.), Charité, Humboldt University Berlin, and Department of Cardiology (M.G.), German Heart Center, Berlin, Germany.
Correspondence to K.-U. Eckardt, MD, Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail kai-uwe.eckardt{at}charite.de
Abstract—The tyrosine kinase
receptor Tie2 (also known as Tek) plays an important role in the
development of the embryonic vasculature and persists in adult
endothelial cells (ECs). Tie2 was shown to be
upregulated in tumors and skin wounds, and its ligands angiopoietin-1
and -2, although they are not directly mitogenic, modulate
neovascularization. To gain further insight into the regulation of
Tie2, we have studied the effect of hypoxia and inflammatory
cytokines, two conditions frequently associated with
neoangiogenic processes, on Tie2 expression in human ECs. Exposure to
1% O2 led to a time-dependent significant rise of Tie2
protein levels in human coronary microvascular
endothelial cells (HCMECs) and dermal
microvascular ECs (HMEC-1) (3.2- and 2.5-fold within 24 hours), which
was reversible after reoxygenation, and induced a less
marked increase in human umbilical vein ECs (HUVECs; 1.7-fold).
Hypoxia-conditioned medium and D-deoxyglucose did
not change Tie2 expression, but desferrioxamine and cobalt, which are
known to mimic hypoxia-sensing mechanisms, induced Tie2 at
ambient oxygen tensions. Tumor necrosis factor-
induced Tie2 in a
time- and dose-dependent fashion in all 3 EC types (HUVEC, 2.3-fold;
HMEC-1, 2.8-fold; and HCMEC, 3.0-fold; 10 ng/mL, 24 hours). Enhanced
expression was also found after exposure to interleukin-1ß (1 ng/mL).
Changes in Tie2 protein levels were paralleled by changes in mRNA
expression. In accordance with these in vitro findings,
immunohistochemistry revealed focal upregulation of Tie2 in capillaries
at the border of infarcted human and rat myocardium. In
conclusion, the data show that hypoxia and inflammatory
cytokines upregulate Tie2, which may contribute to the
angiogenic response in ischemic tissues.
Key Words: receptor, tyrosine kinase • Tie2 • hypoxia • cytokines • endothelium
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