title: Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis.
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 D2receptor 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 D2receptors 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.
authors.affiliation: Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Chandrani
authors.initials: C
authors.lastname: Sarkar
authors.affiliation: Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
authors.affiliation: Stem Cell Research Laboratory, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Pompili
authors.affiliation: Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA. Debanjan.Chakroborty@osumc.edu.
authors.forename: Debanjan
authors.identifier: http://orcid.org/0000-0001-5814-5710
authors.initials: D
authors.lastname: Chakroborty
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005121:Extremities / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis; D010477:Perfusion; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D044140:Receptor, Angiotensin, Type 1; D017448:Receptors, Dopamine D2; D000804:Angiotensin II; D009569:Nitric Oxide; D004298:Dopamine
keywords: Angiogenesis; Angiotensin II; Dopamine; Hind limb ischemia