Cyp1b1-deficient retinal astrocytes are more proliferative and migratory and are protected from oxidative stress and inflammation

Abstract

Astrocytes (ACs) are the most abundant cells in the central nervous system. Retinal ACs play an important role in maintaining the integrity of retinal neurovascular function, and their dysfunction contributes to the pathogenesis of various eye diseases including diabetic retinopathy. Cytochrome P450 1B1 (CYP1B1) expression in the neurovascular structures of the central nervous system including ACs has been reported. We previously showed that CYP1B1 expression is a key regulator of redox homeostasis in retinal vascular cells. Its deficiency in mice resulted in increased oxidative stress and attenuation of angiogenesis in vivo and proangiogenic activity of retinal vascular cells in vitro. Here, using retinal ACs prepared from wild-type ( Cyp1b1+/+) and Cyp1b1-deficient ( Cyp1b1−/−) mice, we determined the impact of Cyp1b1 expression on retinal AC function. We showed that Cyp1b1−/− retinal ACs were more proliferative and migratory. These cells also produced increased amounts of fibronectin and its receptors, αvβ3- and α5β1-integrin. These results were consistent with the increased adhesive properties of Cyp1b1−/− ACs and their lack of ability to form a network in Matrigel. This was reversed by reexpression of Cyp1b1 in Cyp1b1−/− ACs. Although no significant changes were observed in Akt/SRC/MAPK signaling pathways, production of inflammatory mediators bone morphogenetic protein-7 (BMP-7) and monocyte chemoattractant protein-1 (MCP-1) was decreased in Cyp1b1−/− ACs. Cyp1b1−/− ACs also showed increased levels of connexin 43 phosphorylation and cluster of differentiation 38 expression when challenged with H2O2. These results are consistent with increased proliferation and diminished oxidative stress in Cyp1b1−/− cells. Thus, Cyp1b1 expression in ACs plays an important role in retinal neurovascular homeostasis.

Retinal astrocytes transcriptome reveals Cyp1b1 regulates the expression of genes involved in cell adhesion and migration

“…We recently showed that Cyp1b1 deficiency affects retinal AC ECM production and expression of integrin receptors [8]. We also showed upregulation of cadherins, laminin, and tenascin.…”

“…In addition, we observed a significant increase in CD38 expression when Cyp1b1-/-AC were challenged with H 2 O 2 compared with Cyp1b1+/+ cells. Cyp1b1-/-AC also showed enhanced connexin 43 phosphorylation compared with Cyp1b1+/+ cells [8]. Thus, Cyp1b1-deficiency in AC was associated with increased resistance towards oxidative stress.…”

“…We showed Cyp1b1 is constitutively expressed in vascular endothelial cells and perivascular supporting cells from vascular beds of many organs including retina [5,7]. Recently, we also demonstrated that Cyp1b1 is expressed in retinal astrocytes (AC), and Cyp1b1-/-retinal AC are more proliferative and migratory [8]. These cells produced increased amounts of fibronectin and its receptors αvβ3 and α5β1 integrins.…”

Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell–Cell Interactions

“…CYPs are abundant in astrocytes at the blood-brain barrier (BBB), aiding in the regulation of xenobiotic influx into the CNS, blood flow modulation, and signaling during inflammatory conditions [70]. Notably, CYP1B1 is expressed on cerebral micro-vessels and astrocytes at the BBB interface [71,72], and in conjunction with membrane transporters, may aid in regulating xenobiotic passage into and out of the brain. CYP2D6 is expressed in neurons and glial cells [68].…”

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

“…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.…”