Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways

Biochemical studies in endothelial cells (ECs) and genetic studies in mice and humans have yielded major insights into the role of transforming growth factor beta (TGF-beta) and its downstream Smad effectors in embryonic vascular morphogenesis and in the establishment and maintenance of vessel wall integrity. These studies showed that TGF-beta signaling is of critical importance for normal vascular development and physiology. They also indicated the involvement of two distinct TGF-beta signaling cascades within ECs, namely the activin receptor-like kinase 5 (ALK5)-Smad2/3 pathway and the ALK1-Smad1/5 pathway. Aberrant TGF-beta signaling forms the basis for several vascular disorders such as hereditary hemorrhagic telengiectasia and primary pulmonary hypertension as well as neovascularization during tumorigenesis. This review describes the role of TGF-beta in angiogenesis and some of the controversial issues concerning TGF-beta signaling through ALK1 and ALK5 in ECs.