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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2703-2711

CHEMOKINES

Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1

Ombretta Salvucci, Lei Yao, Sabrina Villalba, Agatha Sajewicz, Stefania Pittaluga, and Giovanna Tosato

From the Experimental Transplantation and Immunology Branch and the Laboratory of Pathology, National Cancer Institute, Bethesda, MD.

The chemokine stromal-derived factor-1 (SDF-1) and its unique receptor, CXCR4, are required for normal cardiovascular development, but a critical role for SDF-1 in postnatal vascular remodeling and the mechanisms underlying SDF-1/CXCR-4 vasculogenesis are unclear. Here we show that SDF-1 is expressed by the vascular endothelium from selected healthy and tumor tissues. In vitro, primary endothelial cells constitutively express SDF-1 that is detected in the cytoplasm, on the cell surface, and in the culture supernatant. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) increase SDF-1 expression in endothelial cells. In functional studies, pertussis toxin and antibodies to SDF-1 or CXCR-4 disrupt extracellular matrix-dependent endothelial cell tube formation in vitro. This morphogenic process is associated with time-dependent modulation of surface CXCR-4 expression that changes from being diffuse to being polarized and subsequently lost. In vivo, pertussis toxin and neutralizing antibodies directed at SDF-1 inhibit growth factor-dependent neovascularization. These results indicate that SDF-1/CXCR-4 identifies VEGF- and bFGF-regulated autocrine signaling systems that are essential regulators of endothelial cell morphogenesis and angiogenesis.

© 2002 by The American Society of Hematology.
 

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