Abstract
Purpose :
Central Serous Chorioretinopathy (CSCR) is a pachychoroidal maculopathy that manifests by fluid accumulation between the neurosensory retina and the RPE. CSCR risk gene loci have been identified and there is clinical and experimental evidence that elevated levels of steroid hormones play a pivotal role in CSCR pathogenesis. Here, we investigate risk and steroid receptor gene expression patterns and their distribution across human choroid/ RPE cell types. We aim to decipher potential mechanisms, that might explain the characteristic clinical findings in CSCR patients.
Methods :
Query of scRNA seq data from human choroid/RPE: 15,300 sc transcriptomes from 14 samples: macula and peripheral from 7 donors. Unbiased clustering, dimensionality reduction and visualization using PCA, UMAP, tSNE. Counts per million (CPM) comparison: Mann-Whitney U test between donors, paired t-tests for comparison between mac. and perip. Correlation analysis: Pearson R with p-value adjustment by Benjamini-Hochberg. p<0,05 considered statistically significant.
Results :
Three major results: (1) Expression of the CSCR risk genes PTPRB, CFH, CDH5, TNFRSF10A, ADAMTS9, and NR3C2 is precisely located to the choroidal endothelium, and vascular cell types – not to the RPE. (2) AR (androgen receptor) is significantly higher expressed in the macular endothelium compared to the periphery (expression ratio: er=1,736, p=0,0287). No differential expression was detected for GCCR (glucocorticoid rec.; er=1,317; p=0,0858), MCR (mineralocorticoid rec.; er=0,991; p=0,9172), and PGR (progesterone rec.; er=1,455; p=0,4939). (3) AR expression is positively correlated with CSCR risk gene expression, and with genes coding for VEGF signaling molecules. Among 244 significantly correlated genes, the strongest correlation was detected for RUNX1T1 (Pearson R= 0,096; adjusted p=0,003).
Conclusions :
Our findings are a molecular hint that CSCR initially manifests in the choroidal vasculature, not in the RPE – and thus, should be understood as a vascular eye disease. Furthermore, this article puts androgen hormones in the center of the scientific attention. By illuminating a link to VEGF signaling - RUNX1T1 is a strong mediator of VEGF-A initated angiogenesis and permeability - we might also be able to propose a potential mechanistic explanation for this androgen hypothesis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.