Abstract
Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is essential for the development of new organ systems, but transcriptional control of angiogenesis remains incompletely understood. Here we show that FOXC1 is essential for retinal angiogenesis. Endothelial cell (EC)-specific loss of Foxc1 impairs retinal vascular growth and expression of Slc3a2 and Slc7a5, which encode the heterodimeric CD98 (LAT1/4F2hc) amino acid transporter and regulate the intracellular transport of essential amino acids and activation of the mammalian target of rapamycin (mTOR). EC-Foxc1 deficiency diminishes mTOR activity, while administration of the mTOR agonist MHY-1485 rescues perturbed retinal angiogenesis. EC-Foxc1 expression is required for retinal revascularization and resolution of neovascular tufts in a model of oxygen-induced retinopathy. Foxc1 is also indispensable for pericytes, a critical component of the blood-retina barrier during retinal angiogenesis. Our findings establish FOXC1 as a crucial regulator of retinal vessels and identify therapeutic targets for treating retinal vascular disease.
| Original language | English (US) |
|---|---|
| Article number | 4097 |
| Journal | Nature communications |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
Cdh5-Cre ERT2 mice were kindly provided by Ralf Adams at the Max Planck Institute for Molecular Biology. Bulk RNA-sequencing analysis was performed at The University of Chicago Genomics Facility and bioinformatics analysis was performed by the Northwestern University NUSeq Core Facility. This work was supported by the NIH (RO1HL144129, RO1EY028304 and R01HL159976 to T.K., R01HL148339 to Y.W., and 5T32HL094293 to P.R.N.). Confocal imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Cdh5-Cre mice were kindly provided by Ralf Adams at the Max Planck Institute for Molecular Biology. Bulk RNA-sequencing analysis was performed at The University of Chicago Genomics Facility and bioinformatics analysis was performed by the Northwestern University NUSeq Core Facility. This work was supported by the NIH (RO1HL144129, RO1EY028304 and R01HL159976 to T.K., R01HL148339 to Y.W., and 5T32HL094293 to P.R.N.). Confocal imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
