Abstract
The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs) contribute to the formation of tubes via the generation of sphingosine 1-phosphate (S1P), a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties. Immunofluorescence analysis of human atherosclerotic lesions from carotid endarterectomy showed the colocalization of HNE-adducts with CD31, a marker of endothelial cells, suggesting a close relationship between 4-HNE and neovessel formation. In vitro, low 4-HNE concentration (0.5–1 µM) elicited the formation of tubes by human microvascular endothelial cells (HMEC-1), whereas higher concentrations were not angiogenic. The formation of tubes by 4-HNE involved the generation of reactive oxygen species and the activation of the sphingolipid pathway, namely, the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1) pathway, indicating a role for S1P in the angiogenic signaling of 4-HNE. Carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited the nSMase2/SK1 pathway activation and the formation of tubes on Matrigel® evoked by 4-HNE. Altogether, these results emphasize the role of 4-HNE in the angiogenic effect of oxLDLs and point out the potential interest of pharmacological carbonyl scavengers to prevent the neovascularization process.
Highlights
Angiogenesis, that is, the formation of new capillaries from preexisting blood vessels, is required for embryonic vascular development and wound healing and is involved in the pathophysiology of various diseases, such as diabetic retinopathy, cancer, and atherosclerosis [1]
In atherosclerosis prone areas of coronary arteries, hypercholesterolemia induces neovascularization in Oxidative Medicine and Cellular Longevity the very early steps of intima hyperplasia, before the thickening of the vascular wall [8, 9]. This suggests that, beside the activation of hypoxia-inducible transcription factors that enhance the expression of angiogenic factors [10, 11], some stimuli associated with hypercholesterolemia during early steps of atherosclerosis may induce an angiogenic signaling
Calcein-AM bioreagent, trolox, diphenylene iodonium (DPI), GW4869, Vas2870, and hydralazine were from Sigma, and 4-HNE was from Calbiochem, [methyl-14C]choline-sphingomyelin was from Perkin-Elmer. 5-Carboxy-2,7-dichlorodihydrofluorescein diacetate (H2DCFDA), was from Molecular Probes (Invitrogen France)
Summary
Angiogenesis, that is, the formation of new capillaries from preexisting blood vessels, is required for embryonic vascular development and wound healing and is involved in the pathophysiology of various diseases, such as diabetic retinopathy, cancer, and atherosclerosis [1]. Angiogenesis from vasa vasorum may be induced by an increased thickness of the vascular wall. In atherosclerosis prone areas of coronary arteries, hypercholesterolemia induces neovascularization in Oxidative Medicine and Cellular Longevity the very early steps of intima hyperplasia, before the thickening of the vascular wall [8, 9]. This suggests that, beside the activation of hypoxia-inducible transcription factors that enhance the expression of angiogenic factors [10, 11], some stimuli associated with hypercholesterolemia during early steps of atherosclerosis may induce an angiogenic signaling
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