title: Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis.
abstract: Galectins are carbohydrate binding proteins with versatile functions in tumor progression. Galectin-9, encoded by LGALS9, has been associated with metastasis and immunosuppression. We previously reported on regulation of LGALS9 expression during endothelial cell activation. Here, we show increased galectin-9 protein levels in the endothelium of different tumors, including carcinomas of the lung, liver, breast and kidney. Endothelial cells were found to express five LGALS9 splice variants, two of which have not been reported before. Splicing was found to be confined to exons 5, 6 and 10. Transfection of human microvascular endothelial cells (HMEC) with galectin-9∆5, a specific LGALS9 splice variant, induced a small but significant increase of proliferation, while migration was not affected by any LGALS9 splice variant. Application of recombinant galectin-9∆5 protein dose-dependently reduced proliferation and migration of HMEC as well as human umbilical vein endothelial cells in vitro. Enhanced sprouting and migration of human umbilical vein endothelial cell (HUVEC) towards a galectin-9∆5 gradient were observed. Interestingly, galectin-9∆5 was found to induce a small inhibitory effect on angiogenesis in vivo. Collectively, these data show that endothelial cells regulate the expression and splicing of LGALS9 during angiogenesis. The function of the dominant splice variant, i.e. galectin-9∆5, in endothelial cell biology depends on the concentration and environmental context in which it is presented to the cells.
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Angiogenesis Laboratory, Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Roy
authors: R
authors: Heusschen
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Angiogenesis Laboratory, Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Iris A
authors: IA
authors: Schulkens
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Angiogenesis Laboratory, Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Judy
authors: J
authors: van Beijnum
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Angiogenesis Laboratory, Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Arjan W
authors: AW
authors: Griffioen
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Angiogenesis Laboratory, Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: v.thijssen@vumc.nl.
authors: Victor L
authors: VL
authors: Thijssen
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D037161:Galectins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D037161:Galectins; C105032:LGALS9 protein, human; D020033:Protein Isoforms; D011994:Recombinant Proteins
keywords: Blood vessel; Cancer; Galectin; Vasculature