Cyp1b1 expression impacts the angiogenic and inflammatory properties of liver sinusoidal endothelial cells

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.

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

“…The function of CYP1B1 depends on the oxygen supply. Deletion of CYP1B1 gene is associated with increased oxidative stress in the retinal vascular and trabecular meshwork (TM) cells in culture and retinal and TM tissue in vivo [26]. In the absence of Cyp1b1 in the hepatic sinusoidal endothelial cells prepared from Cyp1b1−/− mice, a low level of hepcidin and decreased production of the bone morphogenetic protein (BMP6) were observed [27,28].…”

Cytochrome P450 1B1: role in health and disease and effect of nutrition on its expression

“…Concluding their ndings, it was stated that CYP1B1 expression had a signicant impact on LSEC angiogenic and inammatory functions. 31 Most recently, the connection between HFD and CYP1B1 modulation in learning and memory decits was described by Zhuanhong and research group in female C57BL/6J mice. The outcomes of their study concluded that Cyp1b1 deciency safeguarded mice from HFD induced cognitive impairment.…”

“…regulation of cellular redox homeostasis and extracellular microenvironment. 31,32 It is postulated that PCG accounts for 55% of primary pediatric glaucoma and is an autosomal recessive disorder which is caused predominantly by mutations in the CYP1B1 gene. 33 Until now, more than 150 mutations in CYP1B1 have been determined linked with PCG that account a signicant fraction of the genetic load of familial and sporadic cases of PCG.…”

Recent Advancements in CD47 Signal Transduction Pathways Involved in Vascular Diseases

“…CD47 can coprecipitate with VEGF, and TSP-1 binding CD47 by the C-terminus can isolate CD47 from VEGFR2 without affecting VEGF binding to VEGFR2, thereby inhibiting downstream AKT activation and activating the functional response of endothelial cells to VEGF to play an antiangiogenic role [37]. VEGF and VEGFR2, as regulators of angiogenesis, are widely expressed in endothelial cells and inflammatory cells such as T cells, and the combination of TSP-1 and CD47 subsequently regulates the expression of VEGF and VEGFR2 [38].…”