Abstract
Galectin-9 consists of two peptide-linked carbohydrate recognition domains (CRDs), but alternative splicing and proteolytic processing can give rise to multiple galectin-9 isoforms. Some of these consist of a single CRD and can exert different functions in cell biology. Here, we explored the role of these galectin-9 isoforms in endothelial cell function and angiogenesis. For this, we compared the effects of the two separate CRDs (Gal-9N and Gal-9C) with the tandem repeat galectin-9M on endothelial cell proliferation, migration, sprouting and tube formation in vitro as well as on angiogenesis in vivo using the chicken chorioallantoic membrane (CAM) assay. Galectin-9 isoforms significantly affected proliferation in quiescent endothelial cells and migration in activated endothelial cells. Interestingly, both monovalent gal-9 CRDs displayed opposite effects compared to gal-9M on proliferation and migration. Sprouting was significantly inhibited by gal-9C, while all isoforms appeared to stimulate tube formation. Angiogenesis in vivo was hampered by all three isoforms with predominant effects on vessel length. In general, the isoforms induced only subtle concentration-dependent effects in vitro as well as in vivo. Collectively, the effects of different galectin-9 isoforms in endothelial cell biology depend on the cellular activation status. While opposing effects can be observed on a cellular level in vitro, all galectin-9 isoforms hamper angiogenesis in vivo. This warrants further investigation of the regulatory mechanisms that underlie the diverging roles of galectin-9 isoforms in endothelial cell biology since this could provide therapeutic opportunities.
Highlights
Galectins are glycan-binding proteins that interact with specific carbohydrate ligands on a variety of substrates, including extracellular matrix proteins, cell surface glycoproteins and glycolipids [1]
We set out to determine the effect of the monovalent galectin-9 carbohydrate recognition domains (CRDs) on endothelial cell function and angiogenesis
This was instigated by the observation that (i) the galectin-9 linker peptide is susceptible to proteolytic cleavage, (ii) both galectin-9 CRDs exert distinct activities on T-cell function, and (iii) endothelial cells express multiple galectin-9 mRNA splice variants, two of which lack the C-terminal CRD
Summary
Galectins are glycan-binding proteins that interact with specific carbohydrate ligands on a variety of substrates, including extracellular matrix proteins, cell surface glycoproteins and glycolipids [1]. Alterations in galectin expression are frequently associated with cancer [2], and members of the galectin family have been linked to different key processes of tumor progression [3, 4]. Galectins are involved in cellular processes like proliferation and apoptosis, thereby contributing to tumor cell transformation [5, 6]. Galectins have been shown to promote tumor progression by facilitating tumor immune escape, tumor metastasis and induction of tumor angiogenesis [3, 4, 7] Regarding the latter, we and others have shown that endothelial cells require galectin-1 for proper function during tumor angiogenesis and that tumor cells can induce angiogenesis by secretion of galectin-1 [8,9,10,11]. Angiostimulatory activity has been ascribed to galectin-3 [12,13,14] and galectin-8 [15]
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