Chronic Stress Induces Rapid Occlusion of Angioplasty-Injured Rat Carotid Artery by Activating Neuropeptide Y and Its Y1 Receptors

Abstract

Objective-We reported previously that neuropeptide Y (NPY) induces an atherosclerotic-like lesion that is significantly reduced by NPY-Y1 and NPY-Y5 receptor (R) inhibitors. Because antagonists also inhibit neointima induced by angioplasty alone, we now test whether stress-induced endogenous NPY release mimic these changes. Methods and Results-Rats were nonstressed or stressed (4°C water; 2 hours per day for 14 days) starting immediately before and continuing after carotid artery angioplasty. Stress acutely and chronically increased blood pressure and doubled plasma NPY levels. After 14 days, angioplasty-induced neointima was markedly greater in stressed (than nonstressed) rats, in which most of the vessels became occluded with an atherosclerotic-like lesion containing macrophages, lipids, thrombus, and microvessels that was similar but more inflammatory than the injury in the NPY-treated vessels. Fourteen days after angioplasty combined with stress or NPY, Y1R and Y5R (mRNA and protein) became upregulated in areas of neointima, microvessels, and macrophages in injured carotid arteries. Stress-and NPY-induced changes were completely prevented by a selective Y1R antagonist (0.02 mol/kg per minute for 14 days), whereas neointima induced by angioplasty alone was reduced by 60%. Conclusions-Because of sympathetic NPY release, stress may be a less-than-appreciated risk factor for restenosis/atherosclerosis, and Y1R antagonists a potential therapy for these conditions. (Arterioscler Thromb Vasc

Of Mice and Men: Neuropeptide Y and Its Receptors Are Associated with Atherosclerotic Lesion Burden and Vulnerability

“…Previously we found that Y1R-mediated mitogenic actions are critical for NPY-and stress-induced neointima formation and vascular occlusion after angioplasty in rats [25,26]. These lesions resembled atherosclerotic plaques as they were also highly neovascularized, and contained macrophages, lipids, and thrombus.…”

“…Y1 receptor is also one of the most abundant vascular receptors constitutively present on VSMCs, and mediates NPY-and stress-induced vasoconstriction, which Y1R antagonists prevent [16]. The same Y1R antagonists have been shown to inhibit neointima formation in animal models of vascular injury, and block potentiating effects of either NPY or stress on it [25,26]. When rats were stressed daily for 1 h by standing in 1 cm deep 4°C water, or when NPY delivered in a slow release pellet on the side of injured artery-both caused occlusion of angioplastyinjured vessel with a neointimal, thromobotic, and vascularized lesion [25,26].…”

“…The same Y1R antagonists have been shown to inhibit neointima formation in animal models of vascular injury, and block potentiating effects of either NPY or stress on it [25,26]. When rats were stressed daily for 1 h by standing in 1 cm deep 4°C water, or when NPY delivered in a slow release pellet on the side of injured artery-both caused occlusion of angioplastyinjured vessel with a neointimal, thromobotic, and vascularized lesion [25,26]. This lesion was rich in matrix, macrophages, and lipid deposition, resembling an advanced atherosclerotic plaque, in spite of the fact that the rats had normal lipid profiles.…”

“…These lesions resembled atherosclerotic plaques as they were also highly neovascularized, and contained macrophages, lipids, and thrombus. Interestingly, the proatherosclerotic effect of NPY in rats was accompanied by increased circulating levels of NPY and in particular, in platelets [25,26] suggesting that platelet-derived NPY may play a pathogenic role in this process.…”

Inhibitory effect of D1-like dopamine receptors on neuropeptide Y-induced proliferation in vascular smooth muscle cells

“…20 Briefly, rats were anesthetized using a mixture of ketamine (80 mg kg − 1 ) and xylazine (12 mg kg − 1 ), and then the left common and external carotid arteries were exposed through a midline cervical incision. A 2F Fogarty catheter (Edwards Life Sciences, Irvine, CA) was introduced into the common carotid artery through an arteriotomy in the external carotid artery and then the catheter was advanced to the proximal edge of the omohyoid muscle.…”