Perivascular nerve fiber α-synuclein regulates contractility of mouse aorta: A link to autonomic dysfunction in Parkinson's disease

Parkinson's disease and other neurodegenerative disorders associated to changes in alpha-synuclein often result in autonomic dysfunction, most of the time accompanied by abundant expression of this synaptic protein in peripheral autonomic neurons. Given that expression of alpha-synuclein in vascular elements has been previously reported, the present study was undertaken to determine whether alpha-synuclein directly participates in the regulation of vascular responsiveness. We detected by immunohistochemistry perivascular nerve fibers containing alpha-synuclein in the aorta of mice while aortic endothelial cells and muscular fibers themselves did not exhibit detectable levels of this protein. To assess the effect of alpha-synuclein on vascular reactivity, aortic ring preparations obtained from alpha-synuclein-deficient knockout mice and from transgenic mice overexpressing human wild-type alpha-synuclein under the control of the tyrosine hydroxylase-promoter were mounted and equilibrated in organ baths for isometric tension recording. Lack of alpha-synuclein did not modify the relaxant responses to the endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilators, but resulted in a greater than normal norepinephrine-induced vasoconstriction along with a lowered response to dopamine, suggesting potential presynaptic changes in dopamine and norepinephrine releases in knockout mice. Overexpression of alpha-synuclein in TH-positive fibers resulted in complex abnormal responses, characterized by lowered acetylcholine-induced relaxation and lowered norepinephrin-induced contraction. Taken together, our data show for the first time that alpha-synuclein is present in sympathetic fibers supplying the murine aorta and provide evidence that changes in alpha-synuclein levels in perivascular fibers play a physiological role in the regulation of vascular function.