Fibronectin-Integrin alpha 5 Signaling in Vascular Complications of Type 1 Diabetes

Vascular complications are a major cause of illness and death in patients with type 1 diabetes (T1D). Diabetic vascular basement membranes are enriched in fibronectin (FN), an extracellular matrix protein that amplifies inflammatory signaling in endothelial cells through its main receptor, integrin alpha 5 beta 1. Binding of the integrin alpha 5 cytoplasmic domain to phosphodiesterase 4D5 (PDE4D5), which increases phosphodiesterase catalytic activity and inhibits antiinflammatory cAMP signaling, was found to mediate these effects. Here, we examined mice in which the integrin alpha 5 cytoplasmic domain is replaced by that of alpha 2 (integrin alpha 5/2) or the integrin alpha 5 binding site in PDE4D is mutated (PDE4D(mut)). T1D was induced via injection of streptozotocin and hyperlipidemia induced via injection of PCSK9 virus and provision of a high-fat diet. We found that in T1D and hyperlipidemia, the integrin alpha 5/2 mutation reduced atherosclerosis plaque size by similar to 50%, with reduced inflammatory cell invasion and metalloproteinase expression. Integrin alpha 5/2 T1D mice also had improved blood-flow recovery from hindlimb ischemia and improved biomechanical properties of the carotid artery. By contrast, the PDE4D(mut) had no beneficial effects in T1D. FN signaling through integrin alpha 5 is thus a major contributor to diabetic vascular disease but not through its interaction with PDE4D.