Of mice and men: neuropeptide Y and its receptors are associated with atherosclerotic lesion burden and vulnerability.

Neuropeptide Y (NPY), a sympathetic and platelet-derived vascular mitogen and angiogenic factor, has been implicated in atherosclerosis in animal and human genetic studies. Here we evaluate its association with human and murine atherosclerosis, and assess the role of platelet-derived NPY in lesion vulnerability. NPY immunoreactivity (NPY-ir) was measured in the platelet-poor and platelet-rich (PRP) plasmas, and NPY receptors (mitogenic Y1R and angiogenic Y2 and Y5Rs), CD26/DPPIV (a protease forming Y2/Y5-selective agonist), CD31-positive vascularity, and lesion morphology assessed by histo- and immunocyto-chemistry-in patients with peripheral artery disease (PAD) and healthy volunteers, and in lard-fed ApoE-/- mice. NPY and NPY-R immunostaining was greater in lesions from PAD patients compared to normal vessels of healthy volunteers (p < 0.001), and localized to smooth muscle cells, macrophages, and adventitial/neovascular endothelial cells. CD26/DPPIV staining co-localized with CD31-positive endothelial cells only in atherosclerotic lesions. NPY-ir in PRP (but not plasma) and vascular immunostaining was higher (p < 0.05 and 0.001, respectively) in men (not women) with PAD compared to healthy subjects. A similar gender specificity was observed in mice. PRP NPY-ir levels correlated with lesion area (p = 0.03), necrotic core area, and the necrotic core-to-lesion area ratio (p < 0.01) in male, but not female, mice. Also males with neovascularized lesions had higher PRP NPY-ir levels than those lacking lesion microvessels (p < 0.05). NPY and its Rs are up-regulated in human and murine atherosclerotic lesions suggesting pathogenic role. DPPIV expression by microvascular endothelium in atherosclerotic tissue may shift NPY's affinity toward angiogenic Y2/Y5Rs, and thus enhance angiogenesis and lesion vulnerability. Remarkably, plaque neovascularization was associated with increased NPY-ir in PRP in males but not females, suggesting that platelet NPY may be a novel mediator/marker of lesion vulnerability particularly in males, for reasons that remain to be determined. Both animal and human data suggest that NPY is an important contributor to, and platelet NPY-ir a marker of, atherosclerotic lesion burden and vulnerability but only in males, perhaps due to androgen-dependent up-regulation of NPY, previously shown in rats.