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Endothelial clock regulates retinal angiogenesis and ganglion cell function

ABSTRACT: Angiogenesis, the formation of new blood vessels from existing ones, is essential for physiological and pathological processes such as wound healing, organ development, and tumor growth. It is a tightly regulated process influenced by both intrinsic and extrinsic factors. Emerging evidence shows a link between biological clocks that regulate physiological rhythms and angiogenesis through the modulation of angiogenic factors like vascular growth factors (Vegfa). Thus, the clock system can directly modulate the timing and efficiency of angiogenic processes. This study aimed to investigate the role of key circadian clock genes, Bmal1 and Per2, in retinal angiogenesis. Endothelial cell specific deletion of these genes significantly impairs vessel growth though distinct phenotypic differences emerge between the two knockout models as angiogenesis progresses. RNA-sequencing (RNA-seq) analysis of retinal endothelial cells reveals that circadian clocks predominantly influence the expression of genes involved in cell proliferation. Notably, vascular endothelial cell (VEC) proliferation is diurnally regulated, which is disrupted in the Bmal1 knockout animals leading to a reduction in the numbers of the Brn3a positive retinal ganglion cells (RGCs). These alterations are further associated with compromised retinal circuitry and function. Thus, this study uncovers critical roles for Bmal1 and Per2 in regulating retinal angiogenesis, emphasizing the importance of circadian control of cell proliferation in vascular development and retinal function.

ORGANISM(S): Mus musculus

PROVIDER: GSE284799 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:The peripheral circadian oscillator plays an essential role in synchronizing local physiology to operate in a circadian manner via regulation of the expression of clock-controlled genes. In the murine uterus, the endometrial stromal cells undergo proliferation and differentiation into decidual cells in response to ovarian steroids and blastocyst implantation at the early stage of pregnancy. The circadian clock genes are attenuated in the decidualizing cells only 2 days after implantation. The present study aimed to evaluate the circadian rhythms of clock genes and clock-controlled genes expressed in the rat uterus endometrial stromal cells (UESCs) during the stage of implantation. The real-time monitoring system of Per2 promoter activity was employed to precisely evaluate the generation of circadian rhythms in the UESCs prepared from transgenic rats constructed with mouse Per2 promoter-destabilized luciferase reporter gene (Per2-dLuc). During monitoring Per2-dLuc oscillation after synchronization with dexamethasone, total RNA was isolated from the cultured UESCs at four-time points (6-h interval) in the first to second phases and cDNA was synthesized. cRNA was synthesized from the double strand cDNA and hybridized on a DNA microarray. RT-qPCR was performed to confirm the expression of core clock genes revealed by DNA microarray analysis. Several clock genes such as Bmal1, Rev-erbα, and Per2 displayed significant rhythms. Of 12,252 genes showing significantly expression, 7,235 genes displayed significant alterations (p < 0.05). These genes were related to growth factors, transcription factors, receptors, channels, and enzymes. Some candidates as clock-controlled genes were evaluated by using RNA interference to Bmal1 mRNA. Down-regulation of Igf1 gene expression was observed by Bmal1 silencing, whereas the expression of Inhβa, Fas, and Caspase3 were significantly increased. These results indicate that clock-controlled genes are up- or down-regulated in rat UESCs during the stage of decidualization. DNA microarray analysis coupled with RNA interference will be helpful to understand the physiological roles of some oscillating genes in blastocyst implantation and placenta formation. The circadian clock positively or negatively regulates the expression of clock-controlled genes, including growth factors and apoptosis-related factors. To search the clock-controlled genes expressed during the period of implantation, we analyzed the clock genes and clock-controlled genes expressed in cultured uterus endometrial stromal cells prepared from pregnant rats at the stage of implantation using DNA microarray technology. We used transgenic rats constructed with mouse Per2 promoter-destabilized luciferase (Per2-dLuc) reporter gene to precisely adjust the time of gene expression. In addition, several genes of significantly expressed genes including growth factor genes and apoptosis-related genes were analyzed using RNA interference to Bmal1 mRNA whether these were controlled under circadian clockwork.

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Endothelial clock regulates retinal angiogenesis and ganglion cell function

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