Expression of hypoxia-inducible angiogenic proteins (hypoxia-inducible factor–1α, vascular endothelial growth factor, and E26 transformation-specific–1) and plaque hemorrhage in human carotid atherosclerosis

Abstract

Object Plaque hemorrhage in carotid atherosclerosis promotes plaque progression, resulting in cerebrovascular disease. Hypoxia inducible factor–1α (HIF-1α) induces angiogenesis via the expression of vascular endothelial growth factor (VEGF) and E26 transformation-specific–1 (Ets-1). The authors investigated human carotid plaques to determine whether these hypoxia-inducible angiogenic proteins play a major role in intraplaque angiogenesis and hemorrhage. Methods The expression of HIF-1α, VEGF, and Ets-1 was analyzed using immunohistochemistry and Western blotting in 29 human carotid plaques obtained at carotid endarterectomy. The authors investigated the relationship between plaque characteristics and clinical symptoms. Results A higher incidence of plaque hemorrhage was observed in plaques associated with symptoms than in those without symptoms (p = 0.03). Hypoxia-inducible factor–1α, VEGF, and Ets-1 coexisted in the deep layer of plaque, where angiogenesis was remarkably developed; the expression levels of HIF-1α, VEGF, and Ets-1 were significantly enhanced in the main lesion of the plaque (p < 0.01). Symptomatic plaques showed higher expression of VEGF (p = 0.04) than asymptomatic plaques. Plaques with hemorrhage showed a higher incidence of plaque ulcer (p = 0.001) and higher expression of Ets-1 (p = 0.03) than those without hemorrhage. Moreover, significantly increased expressions of VEGF (p = 0.01) and Ets-1 (p = 0.006) were observed in plaques with not only hemorrhages but also ulcers and severe stenosis. Conclusions The findings in this study suggest that hypoxia-inducible angiogenic proteins in human carotid atherosclerosis promote intraplaque angiogenesis, which can induce plaque hemorrhage and progression.