SPARC (BM-40, Osteonectin) Inhibits the Mitogenic Effect of Vascular Endothelial Growth Factor on Microvascular Endothelial Cells

Abstract

SPARC (secreted protein, acidic and rich in cysteine)is a matricellular protein that modulates cell adhesion and proliferation and is thought to function in tissue remodeling and angiogenesis. In this study, we demonstrate that SPARC inhibits DNA synthesis by >90% in human microvascular endothelial cells (HMEC) stimulated by the endothelial cell mitogen vascular endothelial growth factor (VEGF). Peptides derived from SPARC domain IV, which contains a disulfide-bonded EF-hand sequence and binds to endothelial cells, mimicked the effect of native SPARC. The inhibition was also observed with a peptide from the follistatin-like domain II, whereas peptides from SPARC domains I and III had no effect on VEGF-stimulated DNA synthesis. The inhibition of HMEC proliferation was mediated in part by the binding of VEGF to SPARC. The binding of 125 I-VEGF to HMEC was reduced by SPARC and SPARC peptides from domain IV in a concentration-dependent manner. In a radioimmune precipitation assay, peptides from SPARC domains II and IV each competed with native SPARC for its binding to VEGF. It has been reported that VEGF stimulates the tyrosine phosphorylation and activation of mitogen-activated protein kinases Erk1 and Erk2. We now show that SPARC reduces this phosphorylation in VEGF-stimulated HMEC to levels of unstimulated controls. SPARC thus modulates the mitogenic activity of VEGF through a direct binding interaction and reduces the association of VEGF with its cell-surface receptors. Moreover, an additional diminution of VEGF activity by SPARC is accomplished through a reduction in the tyrosine phosphorylation of mitogen-activated protein kinases.

Normalization of the Ovarian Cancer Microenvironment by SPARC

“…The anti-inflammatory effects of SPARC have previously been implicated in SP À/À mice as evidenced by decreased leukocyte infiltration in bleomycin-induced peritonitis (79), attenuated 12-O-tetradecanoylphorbol-13-acetate -induced skin inflammation (24), as well as lung and pancreatic tumors, and have been attributed, at least in part, to abundance of less dense, immature collagen fibrils and a more malleable extracellular matrix (19,31). Lastly, SPARC has also been shown to negatively regulate the availability and/or activity of proinflammatory/angiogenic cytokines including platelet-derived growth factor (80), fibroblast growth factor-2 (81), and VEGF (82). Collectively, these data strongly suggest a negative regulatory role for host SPARC in the inflammatory process that accompanies ovarian cancer.…”

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

“…1-3) (Lane et al, 1994;, as it does in other developing tissues, and in tumors and dermal wounds (Lane et al, 1994;Iruela-Arispe et al, 1995;Vajkoczy et al, 2000;Chlenski et al, 2002). SPARC negatively regulates signaling by several angiogenic growth factors, including platelet derived growth factor (Motamed et al, 2002) and vascular endothelial growth factor (Kupprion et al, 1998), but can also be cleaved to produce the potent pro-angiogenic peptide (K)GHK (Lane et al, 1994). Thus, SPARC may function in an anti-or proangiogenic capacity depending on the cellular and extracellular microenvironment.…”

Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma

“…SPARC also has been shown to induce the production of MMP-1 and MMP-9 by monocytes (40). SPARC binds, and is thus an inhibitor of the actions of, vascular endothelial growth factor and platelet-derived growth factor (41)(42)(43) and has been shown to bind collagens, such as types I and IV collagen, and may regulate the synthesis of collagen as well as of other ECM components, such as fibronectin and laminin (35,(44)(45)(46)(47). Thus, it has been postulated that SPARC regulates the deposition or assembly of ECM proteins through the induction of proteases or their inhibitors (43,48).…”