Abstract
Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6″-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells.
Highlights
Angiogenesis is the formation of new blood vessels from pre-existing vessels
We found that debromohamacanthin A (DBHA) significantly inhibited angiogenesis in human umbilical vascular endothelial cells and mouse embryonic stem cell-derived endothelial-like cells as determined by the measurement of cell proliferation and migration, in vitro tube formation and ex vivo vascular sprouting
To determine the anti-angiogenic activity of DBHA, we first evaluated whether DBHA inhibits vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vascular endothelial cells (HUVEC) and mouse embryonic stem (mES)-derived endothelial-like cells
Summary
Angiogenesis is the formation of new blood vessels from pre-existing vessels. Angiogenesis is a multistep process that includes the destabilization of an established vessel and endothelial cell proliferation, migration and tubulogenesis. The binding of VEGF to the VEGFRs and the subsequent ligand-induced dimerization of these receptors stimulate their intrinsic tyrosine kinase activity and trigger key angiogenic responses of endothelial cells, including proliferation, migration and differentiation via a number of signaling cascades [5]. VEGF/VEFGR2-mediated signal transduction is accomplished by the activation of MAPKs including ERK, SAPK/JNK and p38 in endothelial cells. We found that DBHA significantly inhibited angiogenesis in human umbilical vascular endothelial cells and mouse embryonic stem cell-derived endothelial-like cells as determined by the measurement of cell proliferation and migration, in vitro tube formation and ex vivo vascular sprouting. The anti-angiogenic activity was associated with the suppression of the VEGFR2-mediated PI3K/AKT/mTOR signaling pathway
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