Comparative transcriptome analysis of inner blood-retinal barrier and blood–brain barrier in rats

Abstract

Although retinal microvessels (RMVs) and brain microvessels (BMVs) are closely related in their developmental and share similar blood-neural barriers, studies have reported markedly different responses to stressors such as diabetes. Therefore, we hypothesized that RMVs and BMVs will display substantial differences in gene expression levels even though they are of the same embryological origin. In this study, both RMVs and BMVs were mechanically isolated from rats. Full retinal and brain tissue samples (RT, BT) were collected for comparisons. Total RNA extracted from these four groups were processed on Affymetrix rat 2.0 microarray Chips. The transcriptional profiles of these tissues were then analyzed. In the present paper we looked at differentially expressed genes (DEGs) in RMVs (against RT) and BMVs (against BT) using a rather conservative threshold value of ≥ ± twofold change and a false discovery rate corrected for multiple comparisons (p < 0.05). In RMVs a total of 1559 DEGs were found, of which 1004 genes were higher expressed in RMVs than in RT. Moreover, 4244 DEGs between BMVs and BT were identified, of which 1956 genes were ≥ twofold enriched in BMVs. Using these DEGs, we comprehensively analyzed the actual expression levels and highlighted their involvement in critical functional structures in RMVs and BMVs, such as junctional complex, transporters and signaling pathways. Our work provides for the first time the transcriptional profiles of rat RMVs and BMVs. These results may help to understand why retina and brain microvasculature show different susceptibilities to stressors, and they might even provide new insight for pharmacological interventions.

Morphine Accumulates in the Retina Following Chronic Systemic Administration

“…P-gp’s role in transporting morphine from the brain into systemic circulation is well established [ 19 , 20 , 21 , 22 , 23 ]. Significantly, this important transporter is also expressed in the iBRB, albeit at lower levels than in the brain [ 27 , 45 ]. Thus, we wanted to assess the role of P-gp within the context of differential morphine deposition in the retina versus the hypothalamus following systemic exposure.…”

“…The inner blood–retinal barrier (iBRB), the retinal analog of the BBB, expresses the same transporters found at the BBB, which are similarly thought to regulate drug transport between the retina and systemic circulation [ 24 , 25 , 26 ]. Interestingly, the relative expression of P-gp has been shown to be lower in the iBRB compared to the BBB [ 27 ]. However, whether reduced P-gp expression in the retina has functional consequences with regard to retinal morphine deposition remains unknown.…”

Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

“…The iBRB and the BBB share a set of characteristic features, namely tight junctions and a multitude of transporters allowing for directed trans-endothelial movement of solutes in order to compensate for reduced vesicular transport. Although showing many similarities, such as strong expression of tight junction and solute carrier genes, a recent comparative transcriptome analysis revealed some differences between microvessels of the iBRB and the BBB [86]. The expression level of the tight junction-associated genes Cx43, Cx40 and Ocln was shown to be significantly lower in the iBRB than in the BBB, potentially contributing to a higher susceptibility to systemic challenges [86].…”

“…Although showing many similarities, such as strong expression of tight junction and solute carrier genes, a recent comparative transcriptome analysis revealed some differences between microvessels of the iBRB and the BBB [86]. The expression level of the tight junction-associated genes Cx43, Cx40 and Ocln was shown to be significantly lower in the iBRB than in the BBB, potentially contributing to a higher susceptibility to systemic challenges [86]. Indeed, Cx43 has been shown to be crucial for maintaining an intact iBRB and to be declined in hyperglycemia [87,88].…”

“…Indeed, Cx43 has been shown to be crucial for maintaining an intact iBRB and to be declined in hyperglycemia [87,88]. Similarly, the insulin-sensitive glucose transporter gene Slc2a4 (Glut-4) was less strongly expressed in the iBRB than in the BBB, whereas Slc16a1, another member of the Slc family, was enriched in the iBRB [86].…”