Liver sinusoidal endothelial cells in hepatic fibrosis

Abstract

Capillarization, lack of liver sinusoidal endothelial cell (LSEC) fenestration and formation of an organized basement membrane, not only precedes fibrosis, but is also permissive for hepatic stellate cell activation and fibrosis. Thus dysregulation of the LSEC phenotype is a critical step in the fibrotic process. Both a VEGF-stimulated, NO-independent pathway and a VEGF-stimulated NO-dependent pathway are necessary to maintain the differentiated LSEC phenotype. The NO-dependent pathway is impaired in capillarization and activation of this pathway downstream from NO restores LSEC differentiation in vivo. Restoration of LSEC differentiation in vivo promotes HSC quiescence, enhances regression of fibrosis, and prevents progression of cirrhosis.

Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights

“…Serving as a mechanical sieve, fenestration permits steric selection of transfer from sinusoidal space to hepatic parenchyma [6,7]. In addition, SEC show constitutive expression of nitric oxide (NO) synthase, which can be upregulated by increased blood flow and shear stress [8] as well as paracrine factors from other cells such as VEGF [9,10]. Through this mechanism known as autoregulation, hepatic sinusoids can adapt to increased intrahepatic blood flow and decrease intrahepatic pressure [8].…”

“…Besides the canonical pathway of constitutive expression of NO in SEC and its role in the quiescence of HSC [1,19], numerous paracrine and autocrine factors and SEC/HSC crosstalk mechanisms have been identified and discussed in other reviews [1,9,20,21]. Therefore, the following examples of intercellular communication are used illustratively and do not claim to provide a complete overview.…”

“…Thus, reduced NO not only increases intrahepatic resistance, it also plays an important role in the early steps of liver fibrosis [2]. Interdependent with NO, VEGF is a key regulator of SEC phenotype maintenance [9] as it leads to formation and maintenance of fenestrae [1,[37][38][39][40]. Interestingly, VEGF, which is released from hepatocytes and HSC, can act on SEC via both an NO-independent and NO-dependent pathway [10,41].…”

“…Interestingly, VEGF, which is released from hepatocytes and HSC, can act on SEC via both an NO-independent and NO-dependent pathway [10,41]. Of note, only the latter is critical for early steps of liver fibrosis, as reduced NO leads to capillarization and HSC activation in cirrhosis, [9] while VEGF is even upregulated in diseased liver, which can be explained by hypoxic hepatocytes (via HIF1a) and activated HSC secreting VEGF [22,42]. Taken together, the VEGF-stimulated NO-dependent pathway is an illustrative example on how hepatocytes, SEC, and HSC communicate and how interruption of this pathway can lead to fibrogenesis (for details see Fig.…”

Vessels With Cingulin Are Leakproof

“…1,2 Endothelial cells (ECs) specialize their barrier function, as in brain ECs, where the blood-brain barrier protects neurons against toxins, or in liver ECs, where they are highly fenestrated for efficient filtering of the blood. 3 Angiogenesis also relies on regulation of EC junctions. 4 Finally, barrier function plays a role in diseases such as atherosclerosis, where poor barrier maintenance allows increased monocyte extravasation.…”