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Hepatic extraction of solutes depends on microvascular angioarchitecture, hemodynamics and solute concentrations. These factors may contribute to the heterogeneity observed in solute transport and uptake in the hepatic lobules. However, predictions of liver extraction based on black-box models require assumptions about these factors and the microvascular transport mechanisms involved. Consequently, the purpose of this study was to investigate solute transport and uptake by hepatocytes. Livers from male Sprague-Dawley rats were perfused at physiological flowrates and portal pressures on the stage of an in vivo microscope using a low-hematocrit Ringer solution. A bolus of fluorescein isothiocyanate-dextrans (17,900, 39,000, 65,600 or 156,900 MW), which are considered inert fluid-phase markers, was injected into the portal vein. Fluorescein isothiocyanate fluorescence, as a measure of solute concentration, was video recorded in periportal or centrivenular regions of the lobules. Spatial and temporal fluorescence data, measured in sinusoids and hepatocytes, were fit to one-dimensional transport models to determine estimates for an intracellular effective diffusion coefficient and for hepatocyte permeability. The calculated effective diffusion coefficients were 2.5 times larger for dextrans less than 66,000 MW, but were not different between the periportal and centrivenular regions. Also, the values did not show the inverse log-log molecular weight dependency for dextrans seen in other microvascular tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

This investigation is a follow-up to our previous in vivo studies revealing that rapid stretch increases tissue insulin in murine skin flaps, coincident with the up-regulation of key angiogenic effectors and enhanced vascularization. In the present study, we used human umbilical vein endothelial cells (HUVECs) as an in vitro model system to determine the role of insulin in the chemical signals regulating the processes of proliferation and viability (survival). MTT-based colorimetric methods demonstrated that insulin enhances proliferation and survival of HUVECs. Western blot analysis revealed that protein kinase B (pAkt [Thr(308)]) and vascular endothelial growth factor (VEGF) were the insulin-responsive intermediates in proliferating endothelial cells (ECs). In insulin-enhanced survival, both pAkt (Thr(308)) and pAkt (Ser(473)) were activated in HUVECs. However, no change in VEGF expression accompanied pAkt activation. The beneficial effects of insulin were abrogated by insulin receptor (IR)/insulin-like growth factor receptor (IGFR) or phosphoinositide-3 kinase (PI3-K) blockade, suggesting that insulin-induced EC proliferation and viability are mediated through pIR/pIGFR and PI3-K effectors. These data provide new insights into the beneficial effects of insulin on vascularization and tissue viability, providing a mechanistic link to the enhancement of healing in acutely stretched skin.