Angiogenesis: signaling pathways and their inhibitors

Abstract

Angiogenesis refers to the formation of new blood vessels from existing ones and is considered a crucial stage in vascular development. Two distinct types of angiogenesis have been identified: branching and non-branching angiogenesis. This process is involved in both normal physiological and pathological conditions, making it an area of significant interest for biomedical research. The development of angiogenesis involves a series of six stages, each controlled by various microenvironmental factors, such as cytokines and growth factors. These factors can either stimulate (pro-angiogenic) or inhibit (anti-angiogenic) the angiogenesis process. Additionally, ligand-receptor interactions between cells in the vicinity of the site of vessel formation play a role in regulating this intricate process. To date, the precise molecular mechanisms underlying the effects of cytokines, growth factors, and intercellular interactions in angiogenesis have not been fully elucidated. However, studies have demonstrated that signals received by endothelial cells during angiogenesis trigger a series of reactions within these cells, leading to alterations in gene expression and affecting the cellular phenotype and function. These changes influence the nature of vascular formation. The purpose of this review is to summarize current understandings of angiogenesis and its associated molecular mechanisms. The review presents data on the characteristics of endothelial cell populations in growing vessels, the stages of angiogenesis, and the factors that control vascular formation. It highlights the latest findings on signaling pathways such as PI3K/Akt, MARK/ERK, mTOR, RhoA, Ras, Notch, Smad2/3, Smad1/5/8, STАT3, STАT5, NF-κB, and molecules induced in endothelial cells during their interactions with cytokines and growth factors, as well as activation of certain endothelial surface receptors (VEGFR1, VEGFR2, VEGFR3, Tie1, Tie2, FGFR, PDGFR-α, PDGFR-β, TNFR1, TNFR2, VE-cadherin, and TßRI and TßRII. Special attention is given to the interaction between TGF-β signaling and other pathways during angiogenesis. Special attention is given to the description of the interaction between TGFβ signaling and other signaling pathways in angiogenesis. The review also provides current data on inhibitors of these signaling pathways, which can be used in the study of angiogenesis and, if necessary, in its correction during therapy. The review summarizes information on 29 such inhibitors at various stages of development – from in vitro research to clinical applications.