Abstract
Cytochrome P450 1B1 (CYP1B1) is a member of the cytochrome p450 family of enzymes that catalyze mono-oxygenase reactions. Although constitutive Cyp1b1 expression is limited in hepatocytes, its expression and function in liver sinusoidal endothelial cells (LSEC) remains unknown. Here we determined the impact of Cyp1b1 expression on LSEC properties prepared from Cyp1b1+/+ and Cyp1b1-/- mice. LSEC expressed PECAM-1, VE-cadherin, and B4 lectin similar to EC from other mouse tissues. Cyp1b1 +/+ LSEC constitutively expressed significant levels of Cyp1b1, while Cyp1b1-/- LSEC lacked Cyp1b1 expression. LSEC also expressed VEGFR3, PROX-1, and LYVE-1, VEGFR1 and VEGFR2, as well as other cell adhesion molecules including ICAM-1, ICAM-2, VCAM-1, and thrombospondin-1 (TSP1) receptors, CD36 and CD47. However, the expression of PV-1 and stabilin (fenestration markers), and endoglin were limited in these cells. The Cyp1b1-/- LSEC showed limited fenestration, and decreased levels of VEGF and BMP6. Cyp1b1-/- LSEC also showed a decrease in the levels of VE-cadherin and ZO-1 impacting adherens and gap junction formation. Cyp1b1-/- LSEC were significantly more apoptotic, proliferated at a faster rate, and were less adherent and more migratory. These changes were attributed, in part, to decreased amounts of TSP1 and increased AKT and ERK activation. The expressions of integrins were also altered by the lack of Cyp1b1, but the ability of these cells to undergo capillary morphogenesis was minimally affected. Furthermore, Cyp1b1-/- LSEC expressed lower levels of inflammatory mediators MCP-1 and TNF-α. Thus, Cyp1b1 expression has a significant impact on LSEC angiogenic and inflammatory functions.
Highlights
The hepatic sinusoids are covered with blood vessels that perfuse the hepatocytes
We recently showed Cyp1b1 expression is essential during angiogenesis and in proper vascular cell function [33,34,35,36]
We previously showed that Cyp1b1 is constitutively expressed in vascular cells from various tissues, and that lack of Cyp1b1 was associated with increased oxidative stress and attenuation of proangiogenic activity [33, 34, 36, 56]
Summary
The hepatic sinusoids are covered with blood vessels that perfuse the hepatocytes They serve as a location for the oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal vein, and transport blood from the porta hepatis to the inferior vena cava through the liver [1]. Liver sinusoidal endothelial cells (LSEC) are highly specialized and line the hepatic sinusoidal wall [2,3,4]. They are one of the first hepatic cell population that come to contact with blood, separating blood in the sinusoid from the extracellular space of Disse and surrounding hepatocytes [5,6,7]. LSEC play a key role in the regulation of iron homeostasis by expression of bone morphogenic protein 6 (BMP6) and the production of iron regulatory hormone, hepcidin, by hepatocytes [15]
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