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Induction and Analysis of Oxidative Stress in Sleeping Beauty Transposon-Transfected Human Retinal Pigment Epithelial Cells
Published on: December 11, 2020
Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice
Nieves García-Quintans1,2, Cristina Sánchez-Ramos1,3, Ignacio Prieto1
1Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, Room 1.3.2, 28029-, Madrid, Spain.
Abstract:
Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) is a regulator of mitochondrial oxidative metabolism and reactive oxygen species (ROS) homeostasis that is known to be inactivated in diabetic subjects. This study aimed to investigate the contribution of PGC-1α inactivation to the development of oxygen-induced retinopathy. We analyzed retinal vascular development in PGC-1α(-/-) mice. Retinal vasculature of PGC-1α(-/-) mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1α(-/-) mice to hyperoxia during retinal vascular development exacerbated these vascular abnormalities, with extensive retinal hemorrhaging and highly unstructured areas as compared with wild-type mice. Structural analysis demonstrated a reduction in membrane-bound VE-cadherin, which was suggestive of defective intercellular junctions. Interestingly, PGC-1α(-/-) retinas showed a constitutive activation of the VEGF-A signaling pathway. This phenotype could be partially reversed by antioxidant administration, indicating that elevated production of ROS in the absence of PGC-1α could be a relevant factor in the alteration of the VEGF-A signaling pathway. Collectively, our findings suggest that PGC-1α control of ROS homeostasis plays an important role in the regulation of de novo angiogenesis and is required for vascular stability.
Insights
Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) deficiency impairs retinal vascular development and stability. Its inactivation contributes to oxygen-induced retinopathy by disrupting reactive oxygen species homeostasis and altering VEGF-A signaling.
Area of Science:
- Ophthalmology
- Molecular Biology
- Metabolic Regulation
Background:
- Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) regulates mitochondrial metabolism and reactive oxygen species (ROS) homeostasis.
- PGC-1α is inactivated in diabetic subjects, a condition linked to retinopathy.
- The role of PGC-1α in oxygen-induced retinopathy is not well understood.
Purpose of the Study:
- To investigate the contribution of PGC-1α inactivation to the development of oxygen-induced retinopathy.
- To analyze retinal vascular development in PGC-1α deficient mice.
Main Methods:
- Analysis of retinal vascular development in PGC-1α(-/-) mice.
- Exposure of PGC-1α(-/-) mice to hyperoxia.
- Structural analysis of retinal vasculature.
- Assessment of VE-cadherin expression and VEGF-A signaling pathway activation.
Main Results:
- PGC-1α(-/-) mice exhibited reduced pericyte coverage, disorganized vascular plexus, and low perfusion.
- Hyperoxia exposure exacerbated vascular abnormalities in PGC-1α(-/-) mice, causing hemorrhaging and unstructured areas.
- Defective intercellular junctions (reduced VE-cadherin) and constitutive VEGF-A signaling activation were observed in PGC-1α(-/-) retinas.
- Antioxidant administration partially reversed the phenotype, suggesting a role for ROS.
Conclusions:
- PGC-1α inactivation contributes to oxygen-induced retinopathy by impairing retinal vascular development and stability.
- PGC-1α's control of ROS homeostasis is crucial for regulating de novo angiogenesis.
- Maintaining PGC-1α function is essential for vascular stability in the retina.
