SLIT-ROBO Signaling in Diabetes: A Dual Regulator of Angiogenesis and Vascular Dysfunction

Persistent hyperglycemia is a hallmark of diabetes mellitus (DM), a chronic metabolic disease that can lead to peripheral artery disease, retinopathy, nephropathy and other systemic vascular complications. Impaired angiogenesis and compromised vascular integrity are fundamental features of diabetic vascular complications to pathophysiological conditions. Emerging evidence highlights the SLIT/ROBO signaling pathway, which was first identified for its function in axonal guidance and is now recognized as a crucial regulator of angiogenesis and vascular development. In this review, the dualistic role of SLIT/ROBO signaling is discussed with particular emphasis on its context-dependent regulation of angiogenesis, vascular endothelial permeability, and vascular homeostasis. The classical signaling cascade involving SRGAPs/Rho GTPases, as well as its non-classical crosstalk with VEGF, PI3K/Akt, and TGF-β1, illustrate its potential for the regulation of these vascular processes. Evidence from the retina, kidney, brain, and skin will highlight the tissue-specific expression dynamics of SLITs and ROBOs, particularly in the context of hyperglycemic stress. This review discusses the dual role of its member, ROBO4, which has the potential to act as a protective or pathologic factor depending on the vascular microenvironment. In addition, the epigenetic regulation of SLIT2/ROBO signaling through microRNAs, including miR-15a, miR-125b-5p, miR-146a-5p, and miR-411, provide a new perspective, especially with respect to diabetic retinopathy. A deeper understanding of the intricacies of the SLIT/ROBO signaling axis paves the way for further research into SLIT2 mimetics, agonists of its member, ROBO4, as well as microRNA-based therapeutic targets.