Abstract
Persistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty. Human venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury. Exposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (p<0.05), similar to 17R-RvD1. Consistent with pro-resolving activities of other SPM, both 17R-RvD1 and benzo-RvD1 increased the phagocytic activity of RAW 264.7 cells against S. Aureus and Zymosan particles. There were no significant differences in Ki-67 or CD45 staining observed on day 3 after angioplasty. Periadventitial treatment with benzo-RvD1 reduced carotid neointimal area at 14 days compared to control (0.08 mm2 v. 0.18 mm2; p<0.05), with similar efficacy to 17R-RvD1. 17R/S-benzo-RvD1 and 17R-RvD1 exhibit similar pro-resolving and anti-migratory activity in cell-based assays, and both compounds attenuated NIH following acute arterial injury in rats. Further studies of the mechanisms of resolution following vascular injury, and the translational potential of SPM analogues, are indicated.
Highlights
Peripheral arterial disease (PAD) due to atherosclerosis leads to impaired circulation to various areas of the body, most commonly the lower extremities [1]
We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty
specialized pro-resolving lipid mediators (SPM) are derived from the polyunsaturated fatty acids (PUFA) precursors n-6 arachidonic acid (AA), n-3 docosapentaenoic acid (DPA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)
Summary
Peripheral arterial disease (PAD) due to atherosclerosis leads to impaired circulation to various areas of the body, most commonly the lower extremities [1]. Resolution is an active physiologic process that terminates the acute phase of inflammation and promotes the clearance of proinflammatory factors and cellular debris to facilitate tissue repair This process is orchestrated by signaling molecules including specialized pro-resolving lipid mediators (SPM) [9]. SPM are endogenously derived from polyunsaturated fatty acids (PUFA) and act on G-protein coupled receptors present on circulating cells, tissue macrophages and vascular cells [10, 11]. These interactions promote macrophage M2 polarization, limit the expression of adhesion molecules that promote leukocyte accumulation, and enhance the clearance of apoptotic cells and debris, leading to healing rather than chronic inflammation [12–14]. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty
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