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Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis

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Abstract

Increased circulating catecholamines have been linked with cardiovascular anomalies as well as with peripheral vascular diseases. Although the roles of epinephrine and norepinephrine have received considerable attention, the role of the other catecholamine, dopamine, has been less studied. Since dopamine is a potent endogenous inhibitor of angiogenesis and as angiogenesis is essential for ischemic healing, we therefore studied the role played by dopamine during ischemic healing using dopamine D2 receptor knockout (KOD2) mice. Although concentration of dopamine and its rate-limiting enzyme, tyrosine hydroxylase, was considerably high in the muscle tissues of wild-type and KOD2 mice with unilateral hind limb ischemia (HLI), recovery was significantly faster in the KOD2 mice compared to the wild-type controls, thereby indicating that peripheral dopamine might have a role in this healing process. In addition, we observed significant differences in post-ischemic angiogenesis between these two groups. Our study further revealed that elevated dopamine independently suppressed activation of local tissue-based renin-angiotensin system (RAS), a critical growth factor system stimulating angiogenesis in ischemia. Angiotensin II (ATII) and its receptor, angiotensin receptor type 1 (AT1R), are the key players in RAS-mediated angiogenesis. Dopamine acting through its D2 receptors in endothelial cells inhibited ATII-mediated angiogenesis by suppressing the expression of AT1R in these cells. This study thus for the first time demonstrates the role played by dopamine in prolonging post-ischemic recovery. Therefore, pharmacological intervention inhibiting the action of dopamine holds promise as future therapeutic strategy for the treatment of HLI and other peripheral arterial diseases.

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Acknowledgements

The authors thank Dr. Sujit Basu, Department of Pathology and Division of Medical Oncology, Department of Internal Medicine, Ohio State University, for careful reading, insightful comments and suggestions.

Funding

This work is supported by AHA Grant No. 10BGIA4230012 to DC. CS is partly supported by NIH R01 DK098045 and RKG is partly supported by NIH R01 Grants CA109527 and CA153490.

Author contributions

D. C. and C. S. designed research; D. C. and C. S., performed experiments; D. C., C. S., R. K. G. and V. J. P. analyzed data; D. C. and C. S. wrote the paper.

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  1. Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA

    Chandrani Sarkar, Ramesh K. Ganju & Debanjan Chakroborty

  2. Stem Cell Research Laboratory, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

    Vincent J. Pompili

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  1. Chandrani Sarkar
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Sarkar, C., Ganju, R.K., Pompili, V.J. et al. Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis. Angiogenesis 20, 97–107 (2017). https://doi.org/10.1007/s10456-016-9531-8

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