Insight into Retinal Vascular Disease: Genetic Mechanisms May Unveil Therapeutic Targets

Novel genetic mechanisms that regulate blood vessel growth in the retina

Investigators led by Tsutomu Kume, PhD, professor of Medicine in the Division of Cardiology and of Pharmacology, have identified novel genetic mechanisms that regulate blood vessel growth in the retina and may also serve as therapeutic targets for retinal vascular disease, according to a Northwestern Medicine study published in Nature Communications.

What is angiogenesis and why is it important?

Angiogenesis is the process of forming new blood vessels from existing ones, which is essential for developing new organ systems and promoting tissue repair. Although the molecular mechanisms of angiogenesis have been previously established, the precise genetic mechanisms that help regulate this process have remained elusive.

The role of FOXC1 and FOXC2 in retinal angiogenesis

Previous work from Kume’s laboratory and others suggests that mutations in the FOXC1 and FOXC2 genes are associated with various vascular developmental defects. In the current study, the investigators studied retinal tissue from vascular endothelial cell-specific FOXC-knockout mouse lines to determine the role of FOXC1 and FOXC2 in the transcriptional regulation of retinal angiogenesis.

The investigators found that mice with the FOXC1-knockout demonstrated impaired retinal vascular growth and the expression of the SLC3As and SLC7A5 genes, which encode CD98, an essential amino acid transporter. Furthermore, this impaired gene expression inhibited the activation of the mammalian target of rapamycin (mTOR) signaling pathway, which is essential for cellular growth and proliferation.

FOXC1 and revascularization of the retina

Using the oxygen-induced retinopathy mouse model for studying the mechanisms associated with the pathogenesis of retinopathy of prematurity, a major cause of acquired blindness in children, the investigators also found that FOXC1 is necessary for revascularization of the retina during oxygen-induced retinopathy. “This suggests that FOXC1 is also important for the pathological retinal angiogenesis,” said Kume, who is also a professor of Ophthalmology.

Pericytes and the blood-retinal barrier

Additional analyses revealed that FOXC1 is crucial for the maintenance of pericytes, cells that help form the walls of blood vessels. Pericytes also support the blood-retinal barrier during retinal angiogenesis. Pericyte loss is critical for another eye disease: diabetic retinopathy. During disease progression, the blood vessels are damaged and eventually the pericytes are lost, and then the blood vessels become leaky.

Implications for therapeutic strategies

The findings demonstrate that FOXC1 is a key transcriptional regulator for blood vessel growth and the development of the retinal vasculature. The findings may inform future therapeutic strategies for treating retinal vascular disease.

“I am particularly excited about continuing our current collaboration with Dr. Kume to pursue this line of investigation, particularly as it relates to finding new therapeutic targets for diabetic retinopathy and other ischemic retinopathies, and continuing to improve our understanding of these sight-threatening diseases,” said Amani Fawzi, MD, the Cyrus Tang and Lee Jampol Professor of Ophthalmology and a co-author of the study.

Conclusion

The study conducted by Northwestern Medicine identifies novel genetic mechanisms that regulate blood vessel growth in the retina and may serve as therapeutic targets for retinal vascular disease. The study further highlights the role of FOXC1 in transcriptional regulation of retinal angiogenesis, revascularization of the retina during oxygen-induced retinopathy, the maintenance of pericytes which helps form the walls of blood vessels thus supporting the blood-retinal barrier during retinal angiogenesis. With these findings, the study gives insight into developing therapeutic strategies to treat retinal vascular disease.

Keywords:

angiogenesis
retinal vascular disease
genetic mechanisms
FOXC1
FOXC2
transcriptional regulator
oxygen-induced retinopathy
pericytes
blood-retinal barrier
therapeutic strategies
diabetic retinopathy

Originally Post From https://news.feinberg.northwestern.edu/2024/06/10/genetic-mechanisms-may-reveal-retinal-vascular-disease-therapeutic-targets/