Regulation of angiogenesis by the extracellular matrix and protein kinase A

Angiogenesis is a highly regulated process that is regulated by a balance between positive and negative stimuli. Signals transduced by growth factors and integrins promote endothelial cell migration, survival and angiogenesis. In contrast, endothelial cell protein kinase A (PKA) regulates a key pathway that suppresses angiogenesis. Activation of protein kinase A inhibits endothelial cell migration and angiogenesis by suppressing activation of the small GTPase Rac and by inducing endothelial cell apoptosis. Diverse angiogenesis inhibitors such as the naturally occurring hormones parathyroid hormone and parathyroid-hormone-related peptide as well as integrin antagonists activate endothelial cell PKA, thereby inhibiting angiogenesis. Direct activation of PKA by cAMP or by expression of the PKA catalytic subunit also inhibits endothelial cell migration and induces endothelial cell apoptosis, resulting in angiogenesis inhibition in vivo. These studies indicate genetic or pharmacological activation of PKA may be a useful strategy to inhibit angiogenesis.