Mechanobiology of portal hypertension

Abstract

The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies.

Keywords: HSC; LSEC; Liver cirrhosis; hepatic stellate cells; liver fibrosis; liver sinusoidal endothelial cells.

Fig. 1

Strain-related elements of the mechanotransduction cascade. A stiff underlying matrix leads to the formation of focal adhesions, which activate downstream pathways leading to increased contraction of the cytoskeleton. This in turn acts on the nuclear membrane, changing the conformation of nuclear pores and/or leading to epigenetic changes. FAK, focal adhesion kinase; LINC, linker of nucleoskeleton and cytoskeleton; MRTF, myocardin-related transcription factor; ROCK, Rho-associated protein kinase; Y/T, Yes-associated protein 1/WW-domain-containing transcription regulator 1.

Fig. 2

Shear stress and hydrodynamic pressure-related elements of the mechanotransduction cascade in endothelial cells. Blood flow stimulates endothelial cells through hydrodynamic pressure and shear stress, acting directly on the glycocalyx of the cell membranes, indirectly massaging the nucleus via the cytoskeleton network in a cyclic manner. LINC, linker of nucleoskeleton and cytoskeleton.

Fig. 3

Mechanobiology in chronic liver disease and portal hypertension. During the progression of liver disease, several alterations with mechanical consequences take place: excessive extracellular matrix secretion and deposition (fibrosis), altered haemodynamics, sinusoidal hypercontraction, microthrombi, and interstitial oedema. Increase in hepatocyte size by ballooning and steatosis, and cholestasis could be additional features that may contribute to altered mechanosensing. These alterations produce different mechanical forces on the surrounding cells: increased stiffness sensing, distorted shear stress and pathological hydrodynamic pressure. Upon encountering these forces, cells are stretched and/or compressed, stimulating a chronic and pathological de-differentiation. (a)HSCs, (activated) hepatic stellate cells; KCs, Kupffer cells; (d)LSECs, (de-differentiated) liver sinusoidal endothelial cells.