VEGFR2-dependent VEGFR3 expression leads to CXCL1/2 and CXCR2 induction in the development of retinal neovascularization
- 1Department of Physiology, University of Tennessee Health Science Center, 71 S Manassas Street, Memphis, TN 38163 USA
Abstract
Elevated levels of IL-8 have been detected in the vitreous samples of patients with diabetic retinopathy. However, its role in retinal neovascularization remains unknown. We hypothesized that IL-8 and its murine orthologues, CXCL1/2, are key mediators of oxygen-induced retinopathy (OIR)-driven retinal angiogenesis. To this end, we found that VEGFA stimulates CXCL1/2 and their receptor CXCR2 expression in mouse retinal microvascular endothelial cells (MRMVECs) in a time-dependent manner. Recombinant CXCL1/2 induced MRMVEC migration, proliferation, sprouting, and tube formation alone and in combination. Neutralizing CXCL1/2 or CXCR2 antibodies (Abs) attenuated the angiogenic effects of CXCL1/2 as well as VEGFA. In line with these observations in mice, VEGFA induced IL-8 and its receptor CXCR2 expression in human retinal microvascular endothelial cells (HRMVECs), and neutralizing IL-8 or CXCR2 Abs suppressed their angiogenic effects. Furthermore, OIR induced CXCL1/2 and CXCR2 expression in the mouse retina in vivo, and blockade of their function using their neutralizing Abs reduced retinal neovascularization. Mechanistically, depletion of ATF6 or GRP78 levels abrogated VEGFA-induced CXCL1/2 and CXCR2 expression in MRMVECs and IL-8 and CXCR2 expression in HRMVECs in vitro and OIR-induced CXCL1/2 and CXCR2 expression in vivo in mice. Furthermore, silencing VEGFR2 or VEGFR3 levels inhibited VEGFA/OIR-induced ATF6-GRP78 activation and their downstream CXCL1/2, IL-8 and CXCR2 expression both in vitro and in vivo. Together, these findings identify IL-8 as potential therapeutic target for treating retinal neovascular diseases.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10456-026-10104-1.
Related
- Mapping Retinal Gene Expression to Cell Classes: Insights into Retinal Circadian Rhythms.
- Correlating relative light sensitivity to retinal visual gene expression patterns in three African cichlid fish species
- PERK/ATF3-dependent induction of GDE4 modulates intracellular lysophospholipid-PPARα/γ signaling
- SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection
- The African swine fever virus I73R protein is a multifunctional Zα domain that mediates both Z-binding-dependent and -independent biological functions through induction of phase separation
BibTeX
@article{yadavalli2026vegfr2dependent,
title = {{VEGFR2-dependent VEGFR3 expression leads to CXCL1/2 and CXCR2 induction in the development of retinal neovascularization}},
author = {Chandra Sekhar Yadavalli and Raj Kumar and Suresh Govatati and Gadiparthi N. Rao},
journal = {Angiogenesis},
year = {2026},
month = oct,
doi = {10.1007/s10456-026-10104-1},
url = {https://doi.org/10.1007/s10456-026-10104-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - VEGFR2-dependent VEGFR3 expression leads to CXCL1/2 and CXCR2 induction in the development of retinal neovascularization
AU - Chandra Sekhar Yadavalli
AU - Raj Kumar
AU - Suresh Govatati
AU - Gadiparthi N. Rao
PY - 2026
DA - 2026/10/25
JO - Angiogenesis
DO - 10.1007/s10456-026-10104-1
UR - https://doi.org/10.1007/s10456-026-10104-1
AB - Elevated levels of IL-8 have been detected in the vitreous samples of patients with diabetic retinopathy. However, its role in retinal neovascularization remains unknown. We hypothesized that IL-8 and its murine orthologues, CXCL1/2, are key mediators of oxygen-induced retinopathy (OIR)-driven retinal angiogenesis. To this end, we found that VEGFA stimulates CXCL1/2 and their receptor CXCR2 expression in mouse retinal microvascular endothelial cells (MRMVECs) in a time-dependent manner. Recombinant CXCL1/2 induced MRMVEC migration, proliferation, sprouting, and tube formation alone and in combination. Neutralizing CXCL1/2 or CXCR2 antibodies (Abs) attenuated the angiogenic effects of CXCL1/2 as well as VEGFA. In line with these observations in mice, VEGFA induced IL-8 and its receptor CXCR2 expression in human retinal microvascular endothelial cells (HRMVECs), and neutralizing IL-8 or CXCR2 Abs suppressed their angiogenic effects. Furthermore, OIR induced CXCL1/2 and CXCR2 expression in the mouse retina in vivo, and blockade of their function using their neutralizing Abs reduced retinal neovascularization. Mechanistically, depletion of ATF6 or GRP78 levels abrogated VEGFA-induced CXCL1/2 and CXCR2 expression in MRMVECs and IL-8 and CXCR2 expression in HRMVECs in vitro and OIR-induced CXCL1/2 and CXCR2 expression in vivo in mice. Furthermore, silencing VEGFR2 or VEGFR3 levels inhibited VEGFA/OIR-induced ATF6-GRP78 activation and their downstream CXCL1/2, IL-8 and CXCR2 expression both in vitro and in vivo. Together, these findings identify IL-8 as potential therapeutic target for treating retinal neovascular diseases. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10456-026-10104-1.
SN - 0969-6970
SN - 1573-7209
ER -