title: Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways.
abstract: Genetic studies in mice and humans have revealed a pivotal function for transforming growth factor-beta (TGF-β) in vascular development and maintenance of vascular homeostasis. Mice deficient for various TGF-β signaling components develop an embryonic lethality due to vascular defects. In patients, mutations in TGF-β 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-β also has potent direct effects on endothelial cell growth and migration, and we have proposed that TGF-β regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways, activin receptor-like kinase (ALK)1 and ALK5. TGF-β is also critical for the differentiation of mural precursors into pericytes and smooth muscle cells. Furthermore, defective paracrine TGF-β 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-β signaling pathway and its regulation of endothelial and vascular smooth muscle cell function.
authors.affiliation: Department of Molecular Cell Biology, and Centre for Biomedical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands. v.orlova@lumc.nl
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Orlova
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000473:pathology / Q000502:physiology; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014652:Vascular Diseases / Q000473:pathology
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse