title: Aquaporin-1 promotes angiogenesis, fibrosis, and portal hypertension through mechanisms dependent on osmotically sensitive microRNAs.
abstract: Changes in hepatic vasculature accompany fibrogenesis, and targeting angiogenic molecules often attenuates fibrosis in animals. Aquaporin-1 (AQP1) is a water channel, overexpressed in cirrhosis, that promotes angiogenesis by enhancing endothelial invasion. The effect of AQP1 on fibrogenesis in vivo and the mechanisms driving AQP1 expression during cirrhosis remain unclear. The purpose of this study was to test the effect of AQP1 deletion in cirrhosis and explore mechanisms regulating AQP1. After bile duct ligation, wild-type mice overexpress AQP1 that colocalizes with vascular markers and sites of robust angiogenesis. AQP1 knockout mice demonstrated reduced angiogenesis compared with wild-type mice, as evidenced by immunostaining and endothelial invasion/proliferation in vitro. Fibrosis and portal hypertension were attenuated based on immunostaining, portal pressure, and spleen/body weight ratio. AQP1 protein, but not mRNA, was induced by hyperosmolality in vitro, suggesting post-transcriptional regulation. Endothelial cells from normal or cirrhotic mice were screened for microRNA (miR) expression using an array and a quantitative PCR. miR-666 and miR-708 targeted AQP1 mRNA and were decreased in cirrhosis and in cells exposed to hyperosmolality, suggesting that these miRs mediate osmolar changes via AQP1. Binding of the miRs to the untranslated region of AQP1 was assessed using luciferase assays. In conclusion, AQP1 promotes angiogenesis, fibrosis, and portal hypertension after bile duct ligation and is regulated by osmotically sensitive miRs.
authors.affiliation: Gastroenterology Research Unit, Mayo Clinic and Foundation, 200 First St. SW, Rochester, MN 55905, USA. huebert.robert@mayo.edu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Huebert
authors.forename: Kumaravelu
authors.initials: K
authors.lastname: Jagavelu
authors.forename: Helen I
authors.initials: HI
authors.lastname: Hendrickson
authors.forename: Meher M
authors.initials: MM
authors.lastname: Vasdev
authors.forename: Juan P
authors.initials: JP
authors.lastname: Arab
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Splinter
authors.forename: Christy E
authors.initials: CE
authors.lastname: Trussoni
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Larusso
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006975:Hypertension, Portal / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D006982:Hypertonic Solutions / Q000494:pharmacology; D008026:Ligation; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000150:complications* / Q000378:metabolism; D009995:Osmosis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects
chemical_list: D006982:Hypertonic Solutions; D035683:MicroRNAs; D051398:Aquaporin 1