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 position30 (V30M). Until now, the available efficient therapy isliver 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 proteinsinthe 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 exposedto 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Descrição

* This work was supported by Fundação para a Ciencia e Tecnologia Grant PIC/IC/83062/2007. The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database,www.ncbi.nlm.nih.gov/geo (accession no. GSE44856). Supported by Fundação para a Ciencia e Tecnologia (FCT) Fellowship SFRH/BPD/43482/2008. 2 To whom correspondence should be addressed: Angiogenesis Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisbon, Portugal. Tel.: 351-217999411; Fax: 351-217999412; E-mail: sconstantino@fm.ul.pt.

Palavras-chave

Biological effects Disease symptoms Familial amyloidotic polyneuropathy Hepatic artery Liver transplantation Molecular identities Risk factors Transthyretin Amino acids Blood vessels Cell death Disease control Diseases Endothelial cells Proteins Liver prealbumin antiangiogenic activity apoptosis article biological activity cell migration cell survival controlled study down regulation endothelium cell gene expression regulation human human cell nucleotide sequence priority journal protein synthesis Angiogenesis Endothelial Cell Familial Amyloidotic Polyneuropathy Gene Expression Microarray Vascular Biology Allografts Amino Acid Substitution Amyloid Neuropathies, Familial Apoptosis Cell Survival Cells, Cultured Gene Expression Regulation Human Umbilical Vein Endothelial Cells Humans Liver Transplantation Mutation, Missense Neovascularization, Physiologic Prealbumin Thrombosis SDG 3 - Good Health and Well-being