Wnt/beta-catenin signaling induces proliferation, survival and interleukin-8 in human endothelial cells.
Wnts are secreted signaling proteins able to control diverse biological processes such as cell differentiation and proliferation. Many Wnts act through a canonical, beta-catenin signaling pathway. Here, we report that Wnt receptors and transcriptional effectors are expressed in primary human endothelial cells and that Wnt/beta-catenin signaling promotes angiogenesis. Human umbilical vein and microvascular endothelial cells express Wnt receptors, Frizzled-4, -5, -6, and beta-catenin-associated transcription factors, Tcf-1, -3, -4 and Lef-1. In endothelial cells, ectopic expression of Wnt-1 stabilized cytosolic beta-catenin, demonstrating activation of the Wnt/beta-catenin canonical signaling pathway. Expression of Wnt-1 or a stabilized and active form of beta-catenin, beta-cateninS37A, promoted endothelial cell proliferation. Proliferation induced by Wnt/beta-catenin signaling was optimal in the presence of bFGF. beta-cateninS37A expression in endothelial cells promoted survival after growth factor deprivation. Using matrigel assays, Wnt-1 or beta-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/beta-catenin signaling in endothelial cells. Expression of either Wnt-1 or beta-cateninS37A induced Interleukin-8 transcripts and secreted protein. We thus conclude that Wnt/beta-catenin signaling promotes angiogenesis possibly via the induction of known angiogenic regulators such as Interleukin-8.
Masckauchán
T Néstor H
TN
Department of OB/GYN, Columbia University Medical Center, New York, NY 10032, USA.
Shawber
Carrie J
CJ
Funahashi
Yasuhiro
Y
Li
Chi-Ming
CM
Kitajewski
Jan
J
D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D016209:Interleukin-8; D011506:Proteins; D014157:Transcription Factors