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(Circulation Research. 2001;89:1161.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Modulation of Endothelial Cell Growth Arrest and Apoptosis by Vascular Endothelial Growth Inhibitor

Jingyi Yu, Song Tian, Linda Metheny-Barlow, Li-Jin Chew, Andrew J. Hayes, Hongguang Pan, Guo-Liang Yu, Lu-Yuan Li

From the Department of Oncology (J.Y., S.T., L.M.-B., L.-J.C., A.J.H., H.P., L.-Y.L.), Georgetown University Medical Center, Washington, DC, and Mendel Biotechnology (G.-L.Y.), Hayward, Calif.

Correspondence to Lu-Yuan Li, PhD, Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Rd NW, Research Bldg Room E301, Washington, DC 20007-2197. E-mail lilu{at}georgetown.edu

Vascular endothelial growth inhibitor (VEGI), a new member of the tumor necrosis factor family, is an endothelial cell–specific gene and a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. We report here that VEGI mediates the following two activities in endothelial cells: early G₁ arrest in G₀/G₁ cells responding to growth stimuli, and programmed death in proliferating cells. G₀/G₁-synchronized bovine aortic endothelial cells were treated with VEGI before and after the onset of the growth cycle. When the cells were stimulated with growth conditions but treated simultaneously with VEGI, a reversible, early-G₁ growth arrest occurred, evidenced by the lack of late G₁ markers such as hyperphosphorylation of the retinoblastoma gene product and upregulation of the c-myc gene. Additionally, VEGI treatment led to inhibition of the activities of cyclin-dependent kinases CDK2, CDK4, and CDK6. In contrast, VEGI treatment of cells that had entered the growth cycle resulted in apoptotic cell death, as evidenced by terminal deoxytransferase labeling of fragmented DNA, caspase 3 activation, and annexin V staining, all of which were lacking in nonproliferating cells treated with VEGI. Additionally, stress-signaling proteins p38 and JNK were not as fully activated by VEGI in quiescent as compared with proliferating populations. These findings suggest a dual role for VEGI, the maintenance of growth arrest and induction of apoptosis, in the modulation of the endothelial cell cycle.

Key Words: angiogenesis • apoptosis • cell cycle • cytokine • endothelial

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