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Circulation Research. 2003
Published online before print September 4, 2003, doi: 10.1161/01.RES.0000093984.48643.D7
A more recent version of this article appeared on October 3, 2003
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Submitted on April 11, 2003
Revised on July 11, 2003
Accepted on August 18, 2003

Hypoxia-Inducible Factor-1 Mediates Activation of Cultured Vascular Endothelial Cells by Inducing Multiple Angiogenic Factors

Midori Yamakawa ; Louis X. Liu ; Taro Date ; Adam J. Belanger ; Karen A. Vincent ; Geoffrey Y. Akita ; Takayuki Kuriyama ; Seng H. Cheng ; Richard J. Gregory ; and Canwen Jiang *

From Genzyme Corporation (M.Y., L.X.L., T.D., A.J.B., K.A.V., G.Y.A., S.H.C., R.J.G., C.J.), Framingham, Mass; and the Department of Respirology (T.K.), Graduate School of Medicine, Chiba University, Chiba, Japan.

* To whom correspondence should be addressed. E-mail: canwen.jiang{at}genzyme.com.

Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1{alpha} mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1{alpha}/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1{alpha}, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1{alpha}/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1{alpha}/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia- or Ad2/HIF-1{alpha}/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.
Key words: hypoxia-inducible factor-1 • hypoxia • angiogenesis • angiopoietins • vascular endothelial growth factor




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