Vascular complications are a major cause of illness and death in 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 α5β1. Binding of the integrin α5 cytoplasmic domain to phosphodiesterase 4D5 (PDE4D5), which increases PDE catalytic activity and inhibits anti-inflammatory cAMP signaling, was found to mediate these effects. Here, we examined mice in which the integrin α5 cytoplasmic domain is replaced by that of α2 (integrin α5/2) or the integrin α5 binding site in PDE4D is mutated (PDE4Dmut). T1D was induced via injection of streptozotocin and hyperlipidemia induced via injection of PCSK9 virus and high fat diet. We found that in T1D and hyperlipidemia, the integrin α5/2 mutation reduced atherosclerosis plaque size by ∼50%, with reduced inflammatory cell invasion and metalloproteinase expression. Integrin α5/2 T1D mice also showed improved blood flow recovery from hindlimb ischemia and improved biomechanical properties of the carotid artery. By contrast, the PDE4Dmut had no beneficial effects in T1D. FN signaling through integrin α5 is thus a major contributor to diabetic vascular disease but not through its interaction with PDE4D.

中文翻译：

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纤连蛋白-整合素α5信号在1型糖尿病血管并发症中的作用

血管并发症是 1 型糖尿病 (T1D) 疾病和死亡的主要原因。糖尿病血管基底膜富含纤连蛋白 (FN)，这是一种细胞外基质蛋白，可通过其主要受体整合素 α5β1 放大内皮细胞中的炎症信号。发现整合素 α5 胞质结构域与磷酸二酯酶 4D5 (PDE4D5) 的结合可增加 PDE 催化活性并抑制抗炎 cAMP 信号传导，从而介导这些作用。在这里，我们检查了整合素α5 细胞质结构域被α2（整合素α5/2）取代或PDE4D 中整合素α5 结合位点突变（PDE4Dmut）的小鼠。T1D是通过注射链脲佐菌素诱导的，高脂血症是通过注射PCSK9病毒和高脂饮食诱导的。我们发现在 T1D 和高脂血症中，整合素 α5/2 突变使动脉粥样硬化斑块大小减少了约 50%，同时炎症细胞侵袭和金属蛋白酶表达减少。整合素 α5/2 T1D 小鼠还表现出改善后肢缺血后的血流恢复和改善颈动脉的生物力学特性。相比之下，PDE4Dmut 在 T1D 中没有任何有益作用。因此，通过整合素 α5 的 FN 信号传导是糖尿病血管疾病的主要贡献者，但不是通过其与 PDE4D 的相互作用。