Sinusoidal ultrastructure evaluated during the revascularization of regenerating rat liver

Abstract

Sinusoidal endothelial cell (SEC) porosities were compared between the periportal (zone 1) and pericentral (zone 3) regions of the rat liver during regeneration following partial hepatectomy (PHx). SEC porosities and fenestration diameters were measured in control livers, as well as at 5 minutes, 24, 48, 72, 96, 120 hours, and 14 days following PHx. Bimodal maximums in both porosity and fenestration diameters were observed in both zones at 5 minutes and 5 days following PHx. SEC porosities increased significantly in both zones 1 and 3 within 5 minutes following PHx, but the increase was maintained only in zone 1 at 24 hours after resection. Following the initial rise, both zones displayed a gradual decrease to less than half their porosity values at 72 hr post-PHx. After 72 hours, porosities increased to over control levels and remained elevated until 14 days after PHx. The decrease in porosity at 72 hr post-PHx is accompanied by ultrastructural changes within the sinusoid at this time. Vascular corrosion casting and transmission electron microscopy (TEM) show sinusoid compression resulting from increased hepatic plate widths due to hepatocyte proliferation in the absence of SEC proliferation. Also at this time, we observed many SEC completely enveloped by stellate cells. The zonal variations observed for porosities throughout regeneration did not correlate with changes in laminin, collagen I and IV, or fibronectin deposition within the space of Disse. Taken together, the data reveal that SEC are dynamic regulators of porosity that respond rapidly and locally to environmental zonal stimuli during liver regeneration. (HEPATOLOGY 2001;33:363-378.)Following chemical or mechanical injury, the liver has the extraordinary capacity to regenerate back to its normal mass within a short time. During regeneration, the same physiologic functions required by the organism must be performed with less metabolic "equipment," and therefore the liver must continuously adapt its metabolic output to its rapidly changing architecture. As a result of tissue loss, the concentrations of many factors, including growth factors, cytokines, and proteases, rise in the blood and liver to promote temporal and spatial proliferation and migration of the various cells to efficiently reconstitute the liver mass (reviewed by Michalopoulos 1 and Fausto 2 ). Following 70% partial hepatectomy (PHx) in the rat, hepatocyte DNA synthesis peaks abruptly at 24 hours after PHx, and essentially terminates DNA synthesis by 72 hours following resection. 3 Sinusoidal endothelial cells (SEC), the open, fenestrated, discontinuous endothelial cells that line the vessels supplying the parenchymal plates, do not initiate DNA synthesis until 48 to 72 hours after resection, peaking at 4 d post-PHx, but continue to proliferate at least until 8 days following PHx. [3][4][5] This cellular order of proliferative events results in the formation of avascular hepatic islands throughout the liver lobule. 6 Subsequent proliferation and migration of the sinusoidal endothelium i...

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

“…3 confirm that the quantitative decrease in porosity of the sinusoids in arsenic-exposed mice was paralleled by an increased filling of the space of Disse. The images indicate an increased formation of hepatocyte microvilli and similar increases in microvilli have been attributed to a compensatory mechanism to recover lost nutrient uptake (Braet et al, 2002;Wack et al, 2001). The magnified portions of the TEM images showing the space of Disse demonstrate arsenic-stimulated loss of fenestrations and gaps and gain of a rudimentary basement membrane (Fig.…”

“…Samples for TEM were processed as described previously. Stolz et al, 1999;Wack et al, 2001) Ultrathin, 70 nm sections were imaged on a JEM 1210 TEM (JEOL, Peabody, MA) at 80 kV. For SEM, perfused fixed livers were sliced into approximately 3-mm-thick sections, prepared for imaging as described, Stolz et al, 1999;Wack et al, 2001) and imaged with a JSM-6330F scanning electron microscope.…”

Angiogenesis in chronic inflammatory liver disease

“…[33][34][35] Some of the molecular mechanisms involved in hepatic tissue revascularization have been recently unveiled. 30 -32,35-38 Following PH in rodents, hepatocyte proliferation starts, with maximum activity in periportal areas 39 ; reconstruction of sinusoids by ECs begins from these periportal areas.…”

Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration

“…The initial proliferation of hepatocytes leads to the formation of avascular clusters of hepatocytes, in which the central cells reside outside the oxygen diffusion distance of capillaries [24,25]. Hypoxic conditions activate the transcription factor HIF-1, which in turn induces the expression of downstream target genes including c-Met, erythropoietin (EPO), VEGF, and VEGF receptor 1 (VEGFR-1) [26][27][28].…”