Molecular Regulation of Sprouting Angiogenesis

The term angiogenesis arose in the 18th century. Several studies over the next 100 years laid the groundwork for initial studies performed by the Folkman laboratory, which were at first met with some opposition. Once overcome, the angiogenesis field has flourished due to studies on tumor angiogenesis and various developmental models that can be genetically manipulated, including mice and zebrafish. In addition, new discoveries have been aided by the ability to isolate primary endothelial cells, which has allowed dissection of various steps within angiogenesis. This review will summarize the molecular events that control angiogenesis downstream of biochemical factors such as growth factors, cytokines, chemokines, hypoxia-inducible factors (HIFs), and lipids. These and other stimuli have been linked to regulation of junctional molecules and cell surface receptors. In addition, the contribution of cytoskeletal elements and regulatory proteins has revealed an intricate role for mobilization of actin, microtubules, and intermediate filaments in response to cues that activate the endothelium. Activating stimuli also affect various focal adhesion proteins, scaffold proteins, intracellular kinases, and second messengers. Finally, metalloproteinases, which facilitate matrix degradation and the formation of new blood vessels, are discussed, along with our knowledge of crosstalk between the various subclasses of these molecules throughout the text. Compr Physiol 8:153-235, 2018.