Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response

Curcumin is known to be a potent wound healer. Despite this, studies on curcumin using certain model systems have shown it to be anti-angiogenic. Results of the present investigations suggest that curcumin causes opposing effects on angiogenesis in serum stimulated and unstimulated conditions. The evidence in support of this are: (a) in serum free conditions, curcumin promoted sprouting in rat aortic ring, increased vascular density in CAM and induced morphological changes indicative of angiogenic phenotype in HUVECs and rat aortic endothelial cells in culture, (b) increased the expression of biochemical markers of angiogenesis such as CD 31, E-selectin, VEGF and VEGFR-2 in HUVECs on treatment with curcumin, and (c) supplementation of curcumin along with serum caused decrease in CD 31 and E-selectin levels, downregulation of VEGF, angiopoietin-1 and VEGFR-2 and delayed formation of capillary network-like structure. Proangiogenic effect of the individual components of the natural curcumin differed and the presence of the three components in the natural mixture has a synergistic effect. Effect of curcuminoids in the absence of serum appears to depend on VEGF as (a) anti-VEGF antibody blocked the effect of curcuminoids (b) curcuminoids caused decrease in PAR modification of VEGF increasing its biological activity. Treatment with curcuminoids in serum-free conditions resulted in activation of PI3K-Akt pathway; but in serum-supplemented condition, curcuminoids caused inhibition of the MAPK pathways thereby inhibiting the expression of angiogenic phenotype. These results suggest that PI3K-Akt and MAPK pathways involved in the expression of angiogenic phenotype respond differently to the extracellular microenvironment.