Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway — PNAS

Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway

Katarzyna Furrera, Andreas Rickenbachera, Yinghua Tiana, Wolfram Jochumb, Anne Greet Bittermannc, Andres Kächc, Bostjan Humara, Rolf Grafa, Wolfgang Moritza, and Pierre-Alain Claviena,1


+ Author Affiliations

aDepartment of Surgery, Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, and
cCenter for Microscopy and Image Analysis, University of Zurich, CH-8091 Zurich, Switzerland; and
bInstitute of Pathology, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland
Edited* by Jean-Marie P. Lehn, Université Louis Pasteur—Institut de Science et d'Ingénierie Supramoléculaires, Strasbourg Cedex, France, and approved January 7, 2011 (received for review August 25, 2010)


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.

aging liverfenestrationssinusoidal microperfusion

Footnotes

1To whom correspondence should be addressed. E-mail: clavien@access.uzh.ch.

Author contributions: R.G., W.M., and P.-A.C. designed research; K.F., A.R., Y.T., W.J., A.G.B., A.K., and B.H. performed research; K.F., A.R., B.H., R.G., W.M., and P.-A.C. analyzed data; and A.R., B.H., R.G., W.M., and P.-A.C. wrote the paper.

The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.

This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1012531108/-/DCSupplemental.

Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway — PNAS