Resumen de Controlling angiogenesis by two unique TGF-? type I receptor signaling pathways

Valeria V. Orlova, Zhen Liu, Marie-José Goumans, Peter ten Dijke

• Genetic studies in mice and humans have revealed a pivotal function for transforming growth factor-beta (TGF-?) in vascular development and maintenance of vascular homeostasis. Mice deficient for various TGF-? signaling components develop an embryonic lethality due to vascular defects. In patients, mutations in TGF-? receptors have been linked to vascular dysplasia like Hereditary Hemorrhagic Telangiectasia (HHT) and pulmonary arterial hypertension (PAH). Besides indirect effects by regulating the expression of angiogenic regulators, TGF-? also has potent direct effects on endothelial cell growth and migration, and we have proposed that TGF-? regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways, activin receptor-like kinase (ALK)1 and ALK5. TGF-? is also critical for the differentiation of mural precursors into pericytes and smooth muscle cells. Furthermore, defective paracrine TGF-? signaling between endothelial and neighboring mural cells may be responsible for a leaky vessel phenotype that is characteristic of HHT. In this review, we discuss our current understanding of the TGF-? signaling pathway and its regulation of endothelial and vascular smooth muscle cell function.