Transthyretin Proteins Regulate Angiogenesis by Conferring Different Molecular Identities to Endothelial Cells

Familial amyloidotic polyneuropathy (FAP) has a high prevalence in Portugal, and the most common form of hereditary amyloidosis is caused by an amyloidogenic variant of transthyretin (TTR) with a substitution of methionine for valine at position 30 (V30M). Until now, the available efficient therapy is liver transplantation, when performed in an early phase of the onset of the disease symptoms. However, transplanted FAP patients have a significantly higher incidence of early hepatic artery thrombosis compared with non-FAP transplanted patients. Because FAP was described as an independent risk factor for early hepatic artery thrombosis, more studies to understand the underlying mechanisms involved in this outcome are of the utmost importance. Knowing that the liver is the major site for TTR production, we investigated the biological effects of TTR proteins in the vasculature and on angiogenesis. In this study, we identified genes differentially expressed in endothelial cells exposed to the WT or V30M tetramer. We found that endothelial cells may acquire different molecular identities when exposed to these proteins, and consequently TTR could regulate angiogenesis. Moreover, we show that V30M decreases endothelial survival by inducing apoptosis, and it inhibits migration. These findings provide new knowledge that may have critical implications in the prevention of early hepatic artery thrombosis in FAP patients after liver transplantation.

Keywords

Allografts Amino Acid Substitution Amyloid Neuropathies, Familial Cell Survival Cells, Cultured Human Umbilical Vein Endothelial Cells Humans Liver Liver Transplantation Prealbumin Thrombosis Apoptosis Gene Expression Regulation Mutation, Missense Neovascularization, Physiologic

URI

http://hdl.handle.net/10400.7/710

Citation

Raquel J. Nunes, Paula de Oliveira, Ana Lages, Jörg D. Becker, Paulo Marcelino, Eduardo Barroso, Rui Perdigoto, Jeffery W. Kelly, Alexandre Quintas, and Susana Constantino Rosa Santos Transthyretin Proteins Regulate Angiogenesis by Conferring Different Molecular Identities to Endothelial Cells J. Biol. Chem. 2013 288: 31752-. doi:10.1074/jbc.M113.469858