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- Title
Unidirectional crosstalk between Bcl-x<sub>L</sub> and Bcl-2 enhances the angiogenic phenotype of endothelial cells.
- Authors
Karl, E.; Zhang, Z.; Dong, Z.; Neiva, K. G.; Soengas, M. S.; Koch, A. E.; Polverini, P. J.; Núñez, G.; Nör, J. E.
- Abstract
Expression of Bcl-xL correlates with the clinical outcomes of patients with cancer. While the role of Bcl-2 in angiogenesis is becoming increasingly evident, the function of Bcl-xL in angiogenesis is unclear. Here, we showed that epidermal growth factor (EGF) induces in vitro capillary sprouting and Bcl-xL expression in primary endothelial cells. Bcl-xL-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-xL), but not empty vector control cells, spontaneously organize into capillary-like sprouts. Searching for a mechanism to explain these responses, we observed that Bcl-xL induced expression of the pro-angiogenic chemokines CXC ligand-1 (CXCL1) and CXC ligand-8 (CXCL8), and that blockade of CXC receptor-2 (CXCR2) signaling inhibited spontaneous sprouting of HDMEC-Bcl-xL. Bcl-xL led to Bcl-2 upregulation, but Bcl-2 did not upregulate Bcl-xL, suggesting the existence of a unidirectional crosstalk from Bcl-xL to Bcl-2. EGF and Bcl-xL activate the mitogen-activated protein kinase/ERK pathway resulting in upregulation of vascular endothelial growth factor (VEGF), a known inducer of Bcl-2 in endothelial cells. Inhibition of VEGF receptor signaling in HDMEC-Bcl-xL prevented Bcl-2 upregulation and demonstrated the function of a VEGF-mediated autocrine loop. Bcl-2 downregulation by RNAi blocked CXCL1 and CXCL8 expression downstream of Bcl-xL, and markedly decreased angiogenesis in vivo. We conclude that Bcl-xL functions as a pro-angiogenic signaling molecule controlling Bcl-2 and VEGF expression. These results emphasize a complex interplay between Bcl-2 family members beyond their classical roles in apoptosis.Cell Death and Differentiation (2007) 14, 1657–1666; doi:10.1038/sj.cdd.4402174; published online 15 June 2007
- Subjects
VASCULAR endothelial growth factors; ENDOTHELIAL seeding; EPIDERMAL growth factor; CHEMOKINES; GENE expression; APOPTOSIS
- Publication
Cell Death & Differentiation, 2007, Vol 14, Issue 9, p1657
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/sj.cdd.4402174