Endothelial dysfunction in pathological processes of chronic liver disease during aging

Abstract

Aging is associated with gradual changes in liver structure and physiological/pathological functions in hepatic cells including hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). LSECs are specialized hepatic endothelial cells that regulate liver homeostasis. These cells actively impact the hepatic microenvironment as they have fenestrations and a thin morphology to allow substance exchange between circulating blood and the liver tissue. As aging occurs, LSECs have a reduction in both the number and size of fenestrations, which is referred to as pseudocapillarization. This along with the aging of the liver leads to increased oxidative stress, decreased availability of nitric oxide, decreased hepatic blood flow, and increased inflammatory cytokines in LSECs. Vascular aging can also lead to hepatic hypoxia, HSC activation, and liver fibrosis. In this review, we described the basic structure of LSECs, and the effect of LSECs on hepatic inflammation and fibrosis during aging process. We briefly summarized the changes of hepatic microcirculation during liver inflammation, the effect of aging on the clearance function of LSECs, the interactions between LSECs and immunity, hepatocytes or other hepatic nonparenchymal cells, and the therapeutic intervention of liver diseases by targeting LSECs and vascular system. Since LSECs play an important role in the development of liver fibrosis and the changes of LSEC phenotype occur in the early stage of liver fibrosis, the study of LSECs in the fibrotic liver is valuable for the detection of early liver fibrosis and the early intervention of fibrotic response.

The evolving role of liver sinusoidal endothelial cells in liver health and disease

“…[1] In addition, the decrease in NO production in elderly LSECs is associated with the activation of HSCs and profibrotic pathways. [88,89] Interestingly, liver endothelial senescence, dysfunction, and the profibrotic features in aged animals can be attenuated by simvastatin, as well as by the activation of the Sirtuin 1-associated pathway. [1][2][3] Indeed, simvastatin administration to aged rats with cirrhosis reduced portal hypertension, endotheliumdependent vasodilatory capacity, increased LSEC fenestrae, and decreased matrix deposition.…”

The Aging Human Liver: The Weal and Woe of Evolutionary Legacy

“…Moreover, LSECs suffer from increased oxidative stress and ramp up their production of proinflammatory cytokines. Other effects of age-related LSEC changes may include hepatic hypoxia, activation of hepatic stellate cells (HSCs), and liver fibrosis [70]. The latter is due to the well-established role of activated HSCs that are transdifferentiated into profibrotic myofibroblasts producing ECM components [71]; in addition, there is evidence for an involvement of bone marrow-derived myofibroblasts in the development of liver fibrosis [72].…”

Angiocrine Signaling in Sinusoidal Health and Disease

“…This is reversed at a later stage via an autocrine mechanism, as well as increased VEGFR-2 to begin the angiogenic phase. 59 Animal models have demonstrated that, as the angiogenic phase progresses, hepatocytes secrete hypoxia-induced angiogenic factors such as VEGF and angiopoietins that bolster LSEC proliferation until the population reaches its peak at around 3 to 4 days post PHx. 42 60 Finally, LSECs play a key role during the termination phase of liver regeneration by secreting TGF-β, which stimulates HSCs, contributes to reconstruction of the extracellular matrix (ECM) scaffold, and terminates hepatocyte regeneration.…”