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Published on: August 6, 2021
Retinopathy of prematurity shows alterations in Vegfa164 isoform expression
Olachi J Mezu-Ndubuisi1,2, Yong-Seok Song3, Erica Macke4
1Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. olachimezu@pediatrics.wisc.edu.
Insights
Vascular endothelial growth factor-A (VEGF-A) dysregulation drives retinopathy of prematurity (ROP). This study reveals specific VEGF-A isoform overexpression in oxygen-induced ischemic retinopathy (OIR), suggesting new therapeutic targets for ROP.
Area of Science:
- Ophthalmology
- Molecular Biology
- Genetics
Background:
- Pathologic ocular neovascularization in retinopathy of prematurity (ROP) and other proliferative retinopathies is linked to vascular endothelial growth factor-A (VEGF-A) dysregulation.
- Understanding VEGF-A isoform expression in oxygen-induced ischemic retinopathy (OIR) may clarify VEGF dysregulation mechanisms.
Purpose of the Study:
- To investigate the expression patterns of VEGF-A isoforms (Vegfa164a and Vegfa164b) and their receptors (Vegfr1 and Vegfr2) during OIR.
- To elucidate the role of specific VEGF-A isoforms and their receptors in the development of OIR.
Main Methods:
- Oxygen-induced ischemic retinopathy (OIR) was induced in mice.
- Immunohistochemistry and polymerase chain reaction (PCR) were used to analyze Vegfa isoform and receptor expression in room air (RA) and OIR mice at different postnatal days.
- Microglial activation was assessed in OIR and RA mice.
Main Results:
- Total Vegfa mRNA expression increased in OIR mice, peaking at postnatal day 17.
- Vegfa164a and Vegfa164b isoforms were significantly overexpressed in OIR mice during Phase 2 OIR (P16) compared to RA mice.
- Expression of Vegfr1 and Vegfr2, along with increased microglial activation, was observed in OIR mice.
Conclusions:
- Overexpression of Vegfa164a, Vegfa164b, and Vegfr1 in OIR contributes to abnormal signaling and angiogenesis.
- VEGF dysregulation plays a critical role in the ineffective angiogenesis seen in OIR.
- Further research into VEGF dysregulation mechanisms could lead to novel therapies for ROP and other proliferative retinopathies.
Background:
Pathologic ocular neovascularization in retinopathy of prematurity (ROP) and other proliferative retinopathies are characterized by dysregulation of vascular endothelial growth factor-A (VEGF-A). A study of Vegfa isoform expression during oxygen-induced ischemic retinopathy (OIR) may enhance our understanding of Vegf dysregulation.
Methods:
Following induction of OIR, immunohistochemistry and polymerase chain reaction (PCR) was performed on room air (RA) and OIR mice.
Results:
Total Vegfa messenger RNA (mRNA) expression was stable in RA mice, but increased in OIR mice with a peak at postnatal day 17 (P17), before returning to RA levels. Vegfa164a expression was similar in both OIR and RA mice at P10 (Phase 1 OIR), but 2.4-fold higher in OIR mice compared to RA mice at P16 (Phase 2 OIR). At P10, Vegfa164b mRNA was similar in OIR vs RA mice, but was expressed 2.5-fold higher in OIR mice compared to RA mice at P16. At P10 and P16, Vegfr2/Vegfr1 expression was increased in OIR mice compared to RA mice. Increased activation of microglia was seen in OIR mice.
Conclusions:
Vegfa164a, Vegfa164b, and Vegfr1 were overexpressed in OIR mice, leading to abnormal signaling and angiogenesis. Further studies of mechanisms of Vegf dysregulation may lead to novel therapies for ROP and other proliferative retinopathies.
Impact:
Vegfa164 has two major isoforms, a proangiogenic, Vegfa164a, and an antiangiogenic, Vegfa164b, with opposing receptors, inhibitory Vegfr1, and stimulatory Vegfr2, but their role in OIR is unclear. In Phase 1 OIR, both isoforms and receptors are expressed similarly. In Phase 2 OIR, both isoforms are overexpressed, with an increased ratio of inhibitory Vegfr1. Modulation of angiogenesis by Vegf regulation enables pruning of excess angiogenesis during physiology, but results in ineffective angiogenesis during OIR. Knowledge of VEGF dysregulation may have novel therapeutic implications in the management of ROP and retinal proliferative diseases.
