Background—Platelet aggregation plays a critical role in myocardial infarction and stroke; however, the role of platelet secretion in atherosclerotic vascular disease is poorly understood. Therefore, we examined the hypothesis that platelet dense-granule secretion modulates thrombosis, inflammation, and atherosclerotic vascular remodeling after injury.

Methods and Results—Functional deletion of the Hermansky-Pudlak syndrome 3 gene (HPS3^-/-) markedly reduces platelet dense-granule secretion. HPS3^-/- mice have normal platelet counts, platelet morphology, and -granule number, as well as maximal secretion of the -granule marker P-selectin; however, their capacity to form platelet-leukocyte aggregates is significantly reduced (P<0.05). To examine the role of platelet dense-granule secretion in these processes, atherosclerosis-prone mice with combined genetic deficiency of apolipoprotein E and HPS3 (ApoE^-/-, HPS3^-/-) were compared with congenic, atherosclerosis-prone mice with normal platelet secretion (ApoE^-/-, HPS3^+/+). After 16 to 18 weeks on a high-fat diet, both groups of mice had similar fasting cholesterol levels and body weight. Carotid arteries of ApoE^-/-, HPS3^+/+ mice thrombosed rapidly after FeCl₃ injury, but ApoE^-/-, HPS3^-/- mice were completely resistant to thrombotic arterial occlusion (P<0.01). Three weeks after injury, neointimal hyperplasia (from -smooth muscle actin–positive cells) was significantly less (P<0.001) in arteries from ApoE^-/-, HPS3^-/- mice. In ApoE^-/-, HPS3^-/- mice, there were also pronounced reductions in arterial inflammation, as indicated by a 74% decrease in CD45-positive leukocytes (P<0.01) and a 73% decrease in Mac-3–positive macrophages (P<0.05).

Conclusions—In atherosclerotic mice, reduced platelet dense-granule secretion is associated with marked protection against the development of arterial thrombosis, inflammation, and neointimal hyperplasia after vascular injury.