The objective was to investigate whether M3 muscarinic acetylcholine receptor (mAChR) dysfunction disrupts the linkage between the vascular endothelial (VE)-cadherin in the adherens junctional complex and the actin-based cytoskeleton, increasing vascular permeability in atherosclerosis.
Western blotting revealed that a selective M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), and M3 receptor siRNA decrease VE-cadherin and β-catenin in Triton X-100–insoluble fractions, indicating that M3 receptor
inhibition weakens the linkage between the VE-cadherin/β-catenin complex and the actin cytoskeleton. Co-immunoprecipitation assays showed that M3 receptor inhibition reduces Rac1 activity and the association of IQ motif-containing GTPase-activating protein 1 (IQGAP1) with Ras-related
C3 botulinum toxin substrate 1 (Rac1), while increasing the interaction between IQGAP1 and β-catenin. Using IQGAP1 siRNA, we found that IQGAP1 is required for stable interaction between VE-cadherin/β-catenin and the actin cytoskeleton in quiescent endothelial cells; IQGAP1 siRNA
augments the M3 receptor inhibition-induced dissociation between them. Moreover, S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, attenuates this disassociation and Rac1 activity inhibition. The M3 receptor facilitates interaction of the VE-cadherin–based
adherens junctional complex and the actin-based cytoskeleton by maintaining Rac1 activity, which regulates the interaction between IQGAP1/Rac1 and IQGAP1/β-catenin, and may contribute to endothelial barrier function under physiological conditions.
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Document Type: Research Article
Department of Cardiovascular Surgery, Xiehe Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Cardiovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Publication date: January 1, 2014
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