Wnt/β-Catenin Signaling Induces Proliferation, Survival and Interleukin-8 in Human Endothelial Cells

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Abstract
Wnts are secreted signaling proteins able to control diverse biological processes such as cell differentiation and proliferation. Many Wnts act through a canonical, β-catenin signaling pathway. Here, we report that Wnt receptors and transcriptional effectors are expressed in primary human endothelial cells and that Wnt/β-catenin signaling promotes angiogenesis. Human umbilical vein and microvascular endothelial cells express Wnt receptors, Frizzled-4, -5, -6, and β-catenin-associated transcription factors, Tcf-1, -3, -4 and Lef-1. In endothelial cells, ectopic expression of Wnt-1 stabilized cytosolic β-catenin, demonstrating activation of the Wnt/β-catenin canonical signaling pathway. Expression of Wnt-1 or a stabilized and active form of β-catenin, β-cateninS37A, promoted endothelial cell proliferation. Proliferation induced by Wnt/β-catenin signaling was optimal in the presence of bFGF. β-cateninS37A expression in endothelial cells promoted survival after growth factor deprivation. Using matrigel assays, Wnt-1 or β-cateninS37A expression promoted the formation of capillary-like networks. To help define the effectors of Wnt angiogenic function, microarray analysis was used to compare endothelial cells expressing Wnt-1 to control cells. Interleukin-8, a known angiogenic factor, was identified as a transcriptional target of Wnt/β-catenin signaling in endothelial cells. Expression of either Wnt-1 or β-cateninS37A induced Interleukin-8 transcripts and secreted protein. We thus conclude that Wnt/β-catenin signaling promotes angiogenesis possibly via the induction of known angiogenic regulators such as Interleukin-8.