Abstract
Angiogenesis is the formation of new blood vessels from existing vasculature critical for embryonic development and vascular remodeling. Its dysregulation underlies numerous pathologic states ranging from ischemia to tumor growth and as such identifying new targeted- therapies is of significant interest for angiogenesis-based medicine. Here we evaluated the potential angiostatic properties of capsicodendrin (CPCD), a natural compound isolated from Cinnamosma macrocarpa, a plant belonging to the Malagasy Cinnamosma. CPCD potently inhibits endothelial proliferation, migration and capillary tube formation at nanomolar to low micromolar concentrations without inducing cytotoxic effects. We show that CPCD directly inactivates VEGFR2 and downstream AKT signaling, thereby strongly inducing autophagy as determined by increased expression of beclin1, autophagy-related gene (Atg) 3, Atg5 and LC3 cleavage. Ectopic AKT overexpression counteracts the inhibitory effects of CPCD on proliferation and capillary tubule formation. Importantly, CPCD treatment in vivo inhibits sprouting angiogenesis as evidenced by strongly reduced intersegmental vessel (ISV) sprouting and subintestinal vessel (SIV) formation during zebrafish embryonic development, and correlates with increased presence of LC3II along the ISVs despite overall reduced vasculature. These findings demonstrate CPCD as a potent inhibitor of the VEGFR2/AKT pathway at nanomolar concentrations and inducer of autophagy-related angiostatic effects.
Highlights
Angiogenesis is the formation of new blood vessels from pre-existing vasculature, a highly coordinated multi-step process involving endothelial matrix degradation, migration, proliferation and capillary tube formation [1]
A moderate to significant growth-inhibition was observed at concentrations ranging from 100 nM to 2 μM at 48 h (Figure 1A), a result that was recapitulated in a parallel study involving human microvascular endothelial cell 1 (HMEC1) (Figure 1B)
To test whether apoptosis contributed to the overall growth inhibition, annexin-V staining was performed in mouse embryonic endothelial cell line (MEEC) and isolated primary mouse aortic endothelial cells (MAECs)
Summary
Angiogenesis is the formation of new blood vessels from pre-existing vasculature, a highly coordinated multi-step process involving endothelial matrix degradation, migration, proliferation and capillary tube formation [1]. A growing number of small molecules have been identified as promising agents with dozens in preclinical and clinical trials including the flavonoids These and other natural products and metabolites act through multiple interdependent mechanisms including apoptosis, matrix metalloproteinase-2 (MMP2) downregulation, and quite often, by suppressing vascular endothelial growth factor (VEGF) gene expression [13]. While their multitude of inhibitory targets could certainly work in favor of reducing the development of resistance by cancer cells, concerns of unpredictable or undesirable off-target effects remain a significant challenge in clinical settings
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