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Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1
Ombretta Salvucci1, Lei Yao, Sabrina Villalba
1Experimental Transplantation and Immunology Branch and the Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA. salvucco@mail.nih.gov
Insights
Stromal-derived factor-1 (SDF-1) and its receptor CXCR4 regulate blood vessel formation. This study reveals SDF-1/CXCR4 signaling is crucial for endothelial cell growth and new blood vessel development, impacting angiogenesis.
Area of Science:
- Molecular Biology
- Cell Biology
- Cardiovascular Biology
Background:
- The chemokine stromal-derived factor-1 (SDF-1) and its receptor CXCR4 are vital for cardiovascular development.
- The precise role of SDF-1/CXCR4 in postnatal vascular remodeling and vasculogenesis remains unclear.
Purpose of the Study:
- To investigate the role of SDF-1/CXCR4 signaling in endothelial cell morphogenesis and angiogenesis.
- To elucidate the mechanisms of SDF-1/CXCR4-mediated vasculogenesis in response to growth factors.
Main Methods:
- Detection of SDF-1 expression in endothelial cells from healthy and tumor tissues.
- In vitro studies using primary endothelial cells treated with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
- Functional assays involving pertussis toxin and antibodies against SDF-1 or CXCR4 to assess endothelial cell tube formation and in vivo neovascularization.
Main Results:
- SDF-1 is constitutively expressed by endothelial cells and its expression is upregulated by VEGF and bFGF.
- Disruption of SDF-1/CXCR4 signaling inhibited extracellular matrix-dependent endothelial cell tube formation in vitro.
- Pertussis toxin and anti-SDF-1 antibodies suppressed growth factor-induced neovascularization in vivo.
Conclusions:
- SDF-1/CXCR4 signaling constitutes an autocrine system regulated by VEGF and bFGF.
- This signaling pathway is essential for endothelial cell morphogenesis and angiogenesis.
- SDF-1/CXCR4 plays a critical role in postnatal vascular remodeling and neovascularization.
Abstract:
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.