Microglial Galectin3 enhances endothelial metabolism and promotes pathological angiogenesis via Notch inhibition by competitively binding to Jag1

Abstract

Microglia were considered as immune cells in inflammation until their angiogenic role was widely understood. Although the pro-inflammatory role of microglia in retinal angiogenesis has been explored, little is known about its role in pro-angiogenesis and the microglia–endothelia interaction. Here, we report that galectin-3 (Gal3) released by activated microglia functions as a communicator between microglia and endothelia and competitively binds to Jag1, thus inhibiting the Notch signaling pathway and enhancing endothelial angiogenic metabolism to promote angiogenesis. These results suggest that Gal3 may be a novel and effective target in the treatment of retinal angiogenesis.

Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

“… 367 In contrast, JAG1 mediates signal transduction in both tumor cells and endothelial cells, promoting vascular sprouting and higher vascular density. 368 , 369 Liu et al have preliminary evidence confirming JAG1’s pro-angiogenic effect in TNBC, possibly participating in angiogenesis through the enhancement of the MALAT1-miR-1405p-JAG1/VEGFA pathway. 370 This suggests a potential synergistic effect between JAG1 and VEGFA in promoting angiogenesis.…”

The Role of Galectin-3 in Retinal Degeneration and Other Ocular Diseases: A Potential Novel Biomarker and Therapeutic Target

“…Gal3 promotes angiogenesis by interacting with CD146 [68], proteoglycan NG2 [69], and Notch ligand JAG1 [70]. A recent study showed that Gal3 derived from microglia could bind to endothelial Notch ligand, thereby inhibiting the activation of the Notch signaling pathway, interrupting endothelial homeostasis, and promoting retinal neovascularization [71]. In addition, Gal3 interacts with integrin through its carbohydrate recognition domain αVβ3 and then activates a certain signaling pathway to promote the growth of vessels, thereby regulating the angiogenesis mediated by VEGF and basic FGF [72].…”

“…Other studies have reported that Gal3 can exacerbate endothelial dysfunction through a signaling pathway mediated by oxidized low-density lipoprotein receptor-1 (LOX-1) and may also be mediated by the LOX-1/ROS/p38/NF-κB signaling pathway, which induces inflammation and exacerbates endothelial dysfunction [93]. In an oxygen-induced retinopathy model, activated microglia upgrade Gal3, which interacts with Jag1 and blocks the Notch signaling pathway, ultimately disrupting endothelial homeostasis, improving endothelial metabolism, and promoting pathological angiogenesis [71].…”

“…Similarly, several retinal degenerative diseases associated with elevated GFAP and Müller cell gliosis, including light-induced retinal degeneration, are also associated with increased Gal3 expression [5,101]. Gal3 knockout significantly dampened the reactivity of glial cells and preserved photoreceptor cells and ganglion cells [71,109]. Therefore, it could be concluded that in the absence of Gal3, a mere 30% decrease in cerebral blood flow itself would not result in any significant retinal damage.…”

“…The Notch signaling pathway is a key regulator in angiogenesis, and it maintains endothelial homeostasis [139]. Gal3 derived from microglia in ischemic retinopathy could competitively bind to Notch ligand to promote pathological angiogenesis [71]. In addition, elevated serum Gal3 levels in diabetic patients were associated with insulin resistance.…”