title: Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway.
abstract: The function of the liver is well-preserved during the aging process, although some evidence suggests that liver regeneration might be impaired with advanced age. We observed a decreased ability of the liver to restore normal volume after partial hepatectomy in elderly mice, and we identified a pathway that rescued regeneration and was triggered by serotonin. 2,5-dimethoxy-4-iodoamphetamine (DOI), a serotonin receptor agonist, reversed the age-related pseudocapillarization of old liver and improved hepatosinusoidal blood flow. After hepatectomy, the open fenestrae were associated with a restored attachment of platelets to endothelium and the initiation of a normal regenerative response, including the up-regulation of essential growth mediators and serotonin receptors. In turn, hepatocyte proliferation recovered along with regain of liver volume and animal survival. DOI operates through the release of VEGF, and its effects could be blocked with anti-VEGF antibodies both in vitro and in vivo. These results suggest that pseudocapillarization in the aged acts as a barrier to liver regeneration. DOI breaks this restraint through an endothelium-dependent mechanism driven by VEGF. This pathway highlights a target for reversing the age-associated decline in the capacity of the liver to regenerate.
authors.affiliation: Department of Surgery, Laboratory of the Swiss Hepato-Pancreato-Biliary and Transplantation Center, University of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Furrer
authors.forename: Andreas
authors.initials: A
authors.lastname: Rickenbacher
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.forename: Anne Greet
authors.initials: AG
authors.lastname: Bittermann
authors.forename: Andres
authors.initials: A
authors.lastname: Käch
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Moritz
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000367:Age Factors; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D007150:Immunohistochemistry; D008099:Liver / Q000098:blood supply* / Q000502:physiology* / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000502:physiology; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D016133:Polymerase Chain Reaction; D012039:Regional Blood Flow / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000662:Amphetamines; D017366:Serotonin Receptor Agonists; D042461:Vascular Endothelial Growth Factor A; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine