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Toll-like receptor 2 mediates vascular contraction and activates RhoA signaling in vascular smooth muscle cells from STZ-induced type 1 diabetic rats

  • Signaling and cell physiology
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Abstract

Increased vascular smooth muscle cell (VSMC) contraction is an early and critical contributor to the pathogenesis of vascular dysfunction in diabetes; however, knowledge regarding the underlying mechanisms is scarce. Toll-like receptor 2 (TLR2), a well-known component of the innate immunity, is expressed in VSMC and recently has been identified to be systemically activated in diabetes. Whether TLR2 is locally activated in the diabetic blood vessels and have effect on contraction is not known. In the current study, we examined the role of TLR2 in increased vascular contraction in diabetes. Utilizing rat model of type 1 diabetes (induced by streptozotocin (STZ)), we demonstrated that aortas from STZ-diabetic rats exhibit increased expression of TLR2 and its adaptor protein, myeloid differentiation primary response 88 (MyD88), as well as enhanced protein–protein interaction between TLR2 and MyD88, suggesting a TLR2 signaling activation. Blockade of TLR2 in intact aortas using anti-TLR2 antibody attenuated increased vascular contraction in STZ-diabetic rat as assessed by wire myograph. Activation of TLR2 by specific ligand in primary aortic VSMC cultures triggered activation of RhoA which was exacerbated in cells from STZ-diabetic rats than control rats. Activation of RhoA was accompanied by phosphorylation and therefore activation of its downstream targets myosin phosphatase target subunit I and myosin light chain (markers of VSMC contraction). Taken together, these results provide evidence for the role of TLR2 in increased contraction in diabetic blood vessels that involves RhoA signaling. Thus, targeting vascular TLR2 offers a promising drug target to treat vascular dysfunction in diabetes.

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Acknowledgments

The authors would like to thank Lynsey Ekema, MSMI, for assistance with the medical illustration to the figure of this manuscript. We also would like to thank Dr. Maria Tereza Jordao (University of Sao Paulo Brazil), Trevor Hardigan, and Kathryn Spitler (Georgia Regents University) for their assistance in this project, and Jennifer Thompson for editing introduction and discussion. Source of Funding: This work was supported through a research grant from the American Heart Association to M.A.C.S. (13POST14690026).

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The authors declare that they have no conflict of interest.

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  1. Department of Physiology, Georgia Regents University, 1120 Fifteenth St., Augusta, GA, 30912, USA

    Luke Schmidt & Maria Alicia Carrillo-Sepulveda

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  1. Luke Schmidt
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Correspondence to Maria Alicia Carrillo-Sepulveda.

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Schmidt, L., Carrillo-Sepulveda, M.A. Toll-like receptor 2 mediates vascular contraction and activates RhoA signaling in vascular smooth muscle cells from STZ-induced type 1 diabetic rats. Pflugers Arch - Eur J Physiol 467, 2361–2374 (2015). https://doi.org/10.1007/s00424-015-1688-2

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