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.aging liver | fenestrations | sinusoidal microperfusion T he most significant limiting factor for survival after liver surgery and transplantation of a partial graft is the ability of the remnant liver to regenerate (1-3), as documented in human (4, 5) and several animal models (6-8). Although in young patients, small remnant livers (up to 25% of the normal size) can regenerate fully within a few weeks, this process is impaired in the diseased (9, 10) and possibly, older (11) livers.Conventional histological examination of the liver hardly differs between young and old individuals, although a few features have been identified. For example, the size of the liver and the sinusoidal flow decrease with age, akin to the energy stores (glycogen and ATP in hepatocytes) (12-16). It is well-known that there is an age-associated decline in the clearance of a number of drugs (17-19). We have recently shown that protective strategies during liver surgery, such as ischemic preconditioning, are lost in patients older than 65 y of age (14,20,21).Impaired hepatocyte proliferation was also documented in old mice after major hepatectomy, but the impact on animal survival and underlying mechanisms was not evaluated (22). Finally, a study from Japan in recipients of partial grafts showed a lower liver volume 1 wk after transplantation in patients receiving a graft from donors older than 50 y of age (23). Advanced age is also associated with ultrastructural changes in the hepatic sinusoid, called pseudocapillarization, which includes the defenestration (reduction of porosity) and thickening of the sinusoidal endothelium (24-26). Similar findings for the defenestration and capillarization of the hepatic sinusoidal endothelium have been observed in t...

Omega-3 Fatty Acids Protect Fatty and Lean Mouse Livers After Major Hepatectomy

“…Proper endothelial function likewise is a prerequisite for liver regeneration after resection, 35 and the improvement of the defective regeneration seen in aged liver is associated with the reinstallation of vascular integrity. 36 How V3FA's anti-inflammatory action affects liver regeneration is unclear; for example, secretion of tumor necrosis factor (TNF) from Kupffer cells is needed for regeneration, 37 but excess TNF, often elevated in fatty liver, 38 causes liver failure after hepatectomy. 39 Furthermore, targeting inflammatory Kupffer cells has a little effect on regeneration, 40 suggesting that inflammatory contributions to regeneration are more complex than thought.…”

Remote Ischemic Preconditioning

“…Electron microscopy was performed as reported. 10 Histological analyses were performed in a blinded fashion. …”

“…This represents a major knowledge gap, because susceptibility to hepatic IRI is known to increase with age. 9,10 In consideration of an aging population and a growing demand for surgery on elderly liver, 11,12 a clear need exists to establish measures that protect old liver against IR.…”

“…However, we have shown that Vegf administration is able to restore the diminished regenerative capacity of old liver to levels seen in young animals. 10 Therefore, the beneficial effects of RIPC may extend to the protection from hepatic IRI in the elderly.…”

A Standardized Method for the Analysis of Liver Sinusoidal Endothelial Cells and Their Fenestrations by Scanning Electron Microscopy

“…Variation in the selection of sinusoids for micrographs, image analysis of artefacts, and measurement of cell area for porosity and fenestration frequency have led to major discrepancies in published results. A standardized approach for evaluation and measurement of fenestrations and the minimum requirements for data presentation have not been clearly addressed in the literature previously 4,10,[20][21][22][23][24][25][26][27][28][29][30][31] .…”