HISTOLOGY AND HISTOPATHOLOGY

Cellular and Molecular Biology

 

Review

Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways

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

Department of Molecular Cell Biology, and Centre for Biomedical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.

Offprint requests to: Valeria V. Orlova, Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. e-mail: v.orlova@lumc.nl


Summary. 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. Histol Histopathol 26, 1219-1230 (2011)

Key words: Angiogenesis, BMP, Hereditary hemorrhagic telangiectasia, Preeclampsia, Pulmonary arterial hypertension

DOI: 10.14670/HH-26.1219