Rac1, caveolin‐1 and vascular endothelial growth factor ‐mediated liver sinusoidal endothelial cell angiogenesis

In this issue of Liver International, Yokomori et al. (1) detailed how Rac1, a member of the Rho-GTPases protein family, plays a key role in the migration of liver sinusoidal endothelial cells (LSECs) and in the subsequent process of capillary-like tubular formation (i.e. endothelial cell differentiation). The family of Rho-GTPases, thanks to their capacity to regulate actin cytoskeleton dynamics, generally control a wide range of cellular processes, such as cell proliferation, differentiation, motility, membrane transport and cell permeability (2). In fibroblasts and microvascular endothelial cells, Cdc42 produces microspikes and filopodia, Rac1 induces ruffles and lamellipodia, and RhoA promotes stress-fibre formation. The same research group demonstrated the role of RhoA in LSECs in controlling the fenestral diameter (3) – the fenestrae are open, membranebound pores surrounded by a cytoskeletal ring that control the extensive exchange between the liver sinusoidal blood and the hepatocytes. In the present study, Yokomori et al. show in cultured LSECs that Rac1 activity markedly increases with time after continuing exposure to vascular endothelial growth factor (VEGF). In addition, the authors present the first molecular and structural evidence that Rac1 mediates the formation of capillary-like tubular structures when LSECs were exposed to VEGF and grown on matrigel as the cell-culture substrate. The authors postulated that this peculiar cellular rearrangement of LSECs is the first morphological sign of LSEC differentiation, and as such the structural precursor in the complex cascade of LSEC angiogenesis (vide infra). Hence, reviewing Yokomori’s data in light of the recent Rho-GTPases (Rho, Rac and Cdc42) angiogenesis findings by others [for a review, see (4)], illustrates not only the novelty of the data but also highlight that LSECassociated Rho-GTPases might serve as potential molecular targets for treating diseases in which the liver sinusoidal microvasculature plays some major role. For example, the function of Rho-GTPases, or their related downstream effector molecules, are involved in the processes of primary or secondary liver cancer, liver cirrhosis and hepatitis (5). These are all important and severe clinical conditions in which the liver sinusoidal microcirculation is central. Potential therapeutic approaches – involving switching on or off a GTPases-mediated signal-transduction chain – have been recently discussed, reviewed and published in other relevant pathological settings such as cancer (6) and neuro-related diseases (7). Caveolin-1 and angiogenesis