The new anti-actin agent dihydrohalichondramide reveals fenestrae-forming centers in hepatic endothelial cells

Halichondramide and dihydrohalichondramide disrupt microfilaments within 10 minutes and double the number of fenestrae in 30 minutes. Dihydrohalichondramide induces fenestrae-forming centers, whereas halichondramide only revealed fenestrae-forming centers without attached rows of fenestrae with increasing diameter. Correlative microscopy showed the absence of actin filaments (F-actin) in sieve plates and fenestrae-forming centers. Comparable experiments on umbilical vein endothelial cells and bone marrow sinusoidal endothelial cells revealed cell contraction without the appearance of fenestrae or fenestrae-forming centers.(I) A comparison of all anti-actin agents tested so far, revealed that the only activity that misakinolide and dihydrohalichondramide have in common is their barbed end capping activity; (II) this activity seems to slow down the process of fenestrae formation to such extent that it becomes possible to resolve fenestrae-forming centers; (III) fenestrae formation resulting from microfilament disruption is probably unique to LSECs.Liver sinusoidal endothelial cells (LSECs) differ from other endothelial cells. They possess open fenestrae that are grouped in sieve plates and lack a basal lamina [1]. Fenestrae measure about 150 nm and occupy 6–8% of the endothelial surface (porosity) [2,3]. The endothelial filter characteristics determine the exchange between the blood and the hepatocytes, and are affecting the hepatic metabolism of lipoproteins including cholesterol and vitamin A [4]. Structural integrity of the fenestrated sinusoidal liver endothelium is believed to be essential for the maintenance of a normal exchange of fluids, solutes, particles and metabolites between the sinusoidal blood and hepatocytes. In the past, numerous publications appeared about the role of these dynamic structures under various physiological and pathological situations [5]. Their role and involvement in the regenerating liver after partial hepatectomy [6], shear stress [7