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Fibronectin-integrin α5 signaling in vascular complications of type I diabetes

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posted on 2022-06-30, 18:35 authored by Minghao Chen, Rui Hu, Cristina Cavinato, Zhenwu W. Zhuang, Jiasheng Zhang, Sanguk Yun, Pablo Fernandez Tussy, Abhishek Singh, Sae-Il Murtada, Keiichiro Tanaka, Min Liu, Carlos Fernández-Hernando, Jay D. Humphrey, Martin A. Schwartz

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.  

Funding

This work was supported by USPHS grants PO1 HL107205 and a pilot grant from the Yale Diabetes Research Center to MAS. RH was supported by a Chinese Scholar’s Fellowship 201606275182. CF-H was supported by USPHS grant R35HL135820.

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