title: Transthyretin proteins regulate angiogenesis by conferring different molecular identities to endothelial cells.
abstract: 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.
authors.affiliation: From the Angiogenesis Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal.
authors.forename: Raquel J
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Paula
authors.initials: P
authors.lastname: de Oliveira
authors.forename: Ana
authors.initials: A
authors.lastname: Lages
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Becker
authors.forename: Paulo
authors.initials: P
authors.lastname: Marcelino
authors.forename: Eduardo
authors.initials: E
authors.lastname: Barroso
authors.forename: Rui
authors.initials: R
authors.lastname: Perdigoto
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Alexandre
authors.initials: A
authors.lastname: Quintas
authors.forename: Susana Constantino Rosa
authors.initials: SC
authors.lastname: Santos
mesh_terms: D064591:Allografts; D019943:Amino Acid Substitution; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D020125:Mutation, Missense; D018919:Neovascularization, Physiologic; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D011228:Prealbumin
keywords: Angiogenesis; Endothelial Cell; Familial Amyloidotic Polyneuropathy; Gene Expression; Microarray; Transthyretin; Vascular Biology
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