SLIT-ROBO Signaling Acts as a Dual Regulator of Angiogenesis and Vascular Dysfunction in Diabetes

Diabetes mellitus (DM) is a chronic metabolic disease characterized by persistent hyperglycemia, leading to severe systemic vascular complications like peripheral artery disease, retinopathy, and nephropathy. These complications stem from impaired angiogenesis and compromised vascular integrity. Current treatments often fall short in fully addressing these complex vascular pathologies. The SLIT/ROBO signaling pathway, initially known for axonal guidance, has emerged as a critical, yet complex, regulator of vascular development and homeostasis, presenting a potential therapeutic target.

This comprehensive review synthesizes current evidence on the SLIT/ROBO signaling pathway's role in diabetes mellitus and its vascular complications. It examines the dualistic nature of SLIT/ROBO signaling, focusing on its context-dependent regulation of angiogenesis, vascular endothelial permeability, and vascular homeostasis. The review discusses classical SRGAPs/Rho GTPases signaling and non-classical crosstalk with VEGF, PI3K/Akt, and TGF-β1 pathways. It also highlights tissue-specific expression dynamics of SLITs and ROBOs in the retina, kidney, brain, and skin under hyperglycemic stress.

The review elucidates the SLIT/ROBO signaling pathway's dualistic role in diabetic vascular complications, acting as both a protective and pathologic factor depending on the microenvironment.

It highlights how SLIT/ROBO signaling critically regulates angiogenesis, vascular endothelial permeability, and overall vascular homeostasis. The pathway's influence extends through classical cascades involving SRGAPs/Rho GTPases and non-classical interactions with key pro-angiogenic and fibrotic pathways like VEGF, PI3K/Akt, and TGF-β1. Tissue-specific expression of SLITs and ROBOs is observed across the retina, kidney, brain, and skin, with ROBO4 specifically noted for its context-dependent protective or pathologic functions. Furthermore, the review identifies epigenetic regulation of SLIT2/ROBO signaling by microRNAs, including miR-15a, miR-125b-5p, miR-146a-5p, and miR-411, as a significant factor, particularly in diabetic retinopathy.