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Vol. 19, Issue 2, 563-571, February 2008

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Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Anush Oganesian^*, Lucas C. Armstrong, Mary M. Migliorini, Dudley K. Strickland, and Paul Bornstein^*,

Departments of *Biochemistry and Medicine, University of Washington, Seattle, WA 98195; Millipore, Temecula, CA 92590; and The Center for Vascular and Inflammatory Diseases, and the Departments of Surgery and Physiology, University of Maryland, Rockville, MD 20855

Submitted July 10, 2007; Revised October 10, 2007; Accepted November 9, 2007
Monitoring Editor: Josephine Adams

TSPs 1 and 2 function as endogenous inhibitors of angiogenesis. Although thrombospondins (TSPs) have been shown to induce apoptosis in HMVECs, we reasoned that a homeostatic mechanism would also be needed to inhibit EC growth without causing cell death, e.g., in the maintenance of a normal vascular endothelium. HMVECs, cultured in low serum, responded to VEGF with an increase in [³H]thymidine incorporation that was inhibited by TSPs and was accompanied by decreases in the phosphorylation of Akt and MAPK, without an increase in apoptosis. RAP, an inhibitor of the low-density lipoprotein (LDL) family of endocytic receptors, and blocking antibodies to VLDLR were as effective as TSPs in the inhibition of thymidine uptake in response to VEGF, and the effects of these agents were not additive. Supportive evidence for the role of the VLDLR in mediating this inhibition was provided by the demonstration of a high-affinity interaction between TSPs and the VLDLR. We propose that TSP1 and TSP2, together with the VLDLR, initiate a nonapoptotic pathway for maintenance of the normal adult vascular endothelium in a quiescent state, similar to that invoked for the regulation of mitogenesis by PDGF, but involving signaling via the VLDLR rather than LRP1.

Address correspondence to: Paul Bornstein (bornsten{at}u.washington.edu)

Abbreviations used: EC, endothelial cell; HUVEC, human umbilical vein endothelial cell; HMVEC, human microvascular endothelial cell; LDL, low-density lipoprotein; LRP1, low-density lipoprotein–related protein-1; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PTB, phosphotyrosine-binding; RAP, receptor-associated protein; TSP, thrombospondin; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor 2; VLDL, very low density lipoprotein; VLDLR, VLDL receptor.