Genetic mechanisms may reveal therapeutic targets of retinal vascular disease – News Center

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

Angiogenesis is the formation of new blood vessels by endothelial cells in existing blood vessels, an essential process for the development of new organ systems and the promotion of tissue repair. While the molecular mechanisms of angiogenesis have previously been established, the precise genetic mechanisms that also help regulate this process have remained elusive.

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

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

Using the mouse model of oxygen-induced retinopathy to study the mechanisms involved in the pathogenesis of retinopathy of prematurity, a leading cause of acquired blindness in children, the investigators also found that FOXC1 is necessary for retinal revascularization during oxygen-induced retinopathy.

“This suggests that FOXC1 it is also important for the pathological angiogenesis of the retina”, said Kume, who is also a professor of Ophthalmology.

Additional analyzes also revealed that FOXC1 it is essential for the maintenance of pericytes—cells that help form blood vessel walls—and support the blood-retinal barrier during retinal angiogenesis.

“Loss of the pericyte is critical to another eye disease: diabetic retinopathy. During the progression of the disease, blood vessels are damaged and eventually lose pericytes and then the blood vessels leak,” said Kume.

The findings show that FOXC1 is a key transcriptional regulator of vascular growth and retinal vascular development. The findings may inform future therapeutic strategies for the treatment of retinal vascular diseases.

“I am particularly excited about continuing our current collaboration with Dr. We look forward to pursuing this line of inquiry, 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, Cyrus Tang and Lee Jampol Professor of Ophthalmology and a co-author of the study.

“These results not only advance the current understanding of the transcriptional mechanisms that contribute to physiological retinal development, but also identify amino acid metabolism as a potential therapeutic target for the treatment of FOXC1– associated vascular abnormalities, such as cerebral small vessel disease,” the authors wrote.

Teena Bhakuni, PhD, a postdoctoral fellow in Kume’s lab, was the study’s first author. Other co-authors include Can Tan, MD, PhD, research assistant professor of Medicine in the Division of Cardiology.

This work was supported by National Institutes of Health grants RO1HL144129, RO1EY028304, R01HL159976, R01HL148339, and 5T32HL094293.