Calmodulin is essential for angiogenesis in response to hypoxic stress in endothelial cells

Angiogenesis, the formation of new blood vessels that is regulated by hypoxia, is a critical process for the growth and spread of tumors. Multiple phases of this process, including migration, adhesion, and formation of new capillary tubes, are needed for optimal tumor growth. Here, a new regulatory function for Ca2+-CaM in the vascular endothelium is described. Ca2+-CaM activation induced by hypoxia in endothelial cells is essential for angiogenic cellular responses. Inhibition of Ca2+-CaM activity suppressed endothelial cell migration, adhesion on collagen I substrate, invasion and impaired in vitro endothelial cell differentiation into tube-like structures. We also reported that CaM is co-distributed with the actin structures in the lamellipodia in migrating cells, whereas the actin cytoskeleton rearrangement induced by hypoxia was disrupted and HIF-1 transcriptional activity was decreased when treated with CaM antagonists into cultures. These data indicate that Ca2+-CaM activation is more closely associated with the regulation of angiogenic key events, especially in response to hypoxic stress.