| First Author | Warboys CM | Year | 2014 |
| Journal | Cardiovasc Res | Volume | 104 |
| Issue | 1 | Pages | 116-26 |
| PubMed ID | 25062958 | Mgi Jnum | J:230109 |
| Mgi Id | MGI:5755527 | Doi | 10.1093/cvr/cvu173 |
| Citation | Warboys CM, et al. (2014) Bidirectional cross-regulation between the endothelial nitric oxide synthase and beta-catenin signalling pathways. Cardiovasc Res 104(1):116-26 |
| abstractText | AIMS: beta-catenin has been shown to be regulated by inducible nitric oxide synthase (NOS) in endothelial cells. We investigated here whether beta-catenin interacts with and regulates endothelial NOS (eNOS) and whether eNOS activation promotes beta-catenin signalling. METHODS AND RESULTS: We identified beta-catenin as a novel eNOS binding protein in human umbilical vein endothelial cells (HUVECs) by mass spectroscopy and western blot analyses of beta-catenin and eNOS immunoprecipitates. This was confirmed by in situ proximity ligation assay. eNOS activity, assessed by cGMP production and eNOS phosphorylation (Ser1177), was enhanced in beta-catenin(-/-) mouse pulmonary endothelial cells (MPECs) relative to wild-type MPECs. eNOS activation (using adenosine, salbutamol, thrombin, or histamine), or application of an NO donor (spermine NONOate) or cGMP-analogue (8-bromo-cGMP) caused nuclear translocation of beta-catenin in HUVEC as shown by western blotting of nuclear extracts. Exposure to spermine NONOate, 8-bromo-cGMP, or sildenafil (a phosphodiesterase type 5 inhibitor) also increased the expression of beta-catenin-dependent transcripts, IL-8, and cyclin D1. Stimulation of wild-type MPECs with basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), spermine NONOate, 8-bromo-cGMP, or sildenafil increased tube length relative to controls in an angiogenesis assay. These responses were abrogated in beta-catenin(-/-) MPECs, with the exception of that to bFGF which is NO-independent. In C57BL/6 mice, subcutaneous VEGF-supplemented Matrigel plugs containing beta-catenin(-/-) MPECs exhibited reduced angiogenesis compared with plugs containing wild-type MPECs. Angiogenesis was not altered in bFGF-supplemented Matrigel. CONCLUSION: These data reveal bidirectional cross-talk and regulation between the NO-cGMP and beta-catenin signalling pathways. |
