Abstract
While usually described together, the true link between stress and the onset of atherosclerosis has yet to be elucidated. Neuropeptide Y (NPY), a sympathetic neurotransmitter and vascular growth factor, exhibits a human gene polymorphism associated with accelerated atherosclerosis, and in mice, induces atherosclerotic-like lesions after angioplasty. We have found that NPY is a mitogen for smooth muscle cells in vitro. Further, platelet NPY immunoreactivity levels increase after stress by approximately 12%. These findings suggest megakaryocytes influence the increase in NPY mRNA after stress, as detected by quantitative RT-PCR. Sympathetic activation and NPY release was induced by cold stress of 1hr/day/14days in 4°C water, and when combined with angioplasty, resulted in increased neointimal formation and vascular occlusive lesions. Therefore, we hypothesize that stress promotes vascular occlusion after angioplasty by activating a novel neuronal-megakaryocyte axis, leading to increased platelet NPY levels, which is pro-atherosclerotic. Time trials of 1, 3, 7, and 14 days resulted in a 2–4 fold increase of neointimal formation over time, as compared to NPY-KO studies. Platelet transfer experiments from wild-type to NPY KO mice (and vice-versa) validated the role of platelet NPY in neoinitmal formation after angioplasty. We conclude that stress up-regulates NPY expression in megakaryocytes, likely via a sympathetic link, as shown by positive immunohistochemical co-localization staining for synapsin, CD41 and tyrosine hydroxylase in bone marrow, leading to increased platelet NPY and neointimal formation. Thus, platelet NPY may serve as an important factor linking stress to atherosclerosis after angioplasty.
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