Furrer, K; Rickenbacher, A; Tian, Y; Jochum, W; Bittermann, A G; Käch, A; Humar, B; Graf, R; Moritz, W; Clavien, P A (2011). Serotonin reverts age-related capillarization and failure of regeneration in the liver through a VEGF-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 108(7):2945-2950.
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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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research|
04 Faculty of Medicine > Center for Microscopy and Image Analysis
04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||18 Feb 2011 09:09|
|Last Modified:||23 Nov 2012 14:22|
|Publisher:||National Academy of Sciences|
|WoS Citation Count:||12|
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