17R/S-Benzo-RvD1, a synthetic resolvin D1 analogue, attenuates neointimal hyperplasia in a rat model of acute vascular injury

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Addition of Resolvins D1 or E1 to Collagen Membranes Mitigates Their Resorption in Diabetic Rats

“…Our data indicate that SPMs are able not only to dampen inflammation in tissues located adjacent to the point of delivery [56][57][58]61,66,68,[71][72][73], but also to protect medical devices that carry them from being resorbed prematurely in circumstances characterized by a high degree of collagenolysis. Preventing the resorption of bioresorbable medical devices prolongs their survival and improves their functionality in terms of both separating and supporting tissues and their ability to deliver biologics.…”

“…Local injuries (such as skin wounds, vascular injuries, dental injuries, etc.) that result in inflammation can also be treated by delivering SPMs locally to the injured area or via a variety of implantable medical devices [56][57][58][59][60][61]66,68,[71][72][73].…”

“…Positive effects of resolvins delivered via various dressings on wound healing were found in mice. Other studies have shown beneficial effects of local resolvin delivery in surgical models of vascular injury in rats and rabbits [56][57][58].…”

Lipid mediators in neutrophil biology: inflammation, resolution and beyond

“…Each SPMs displays potent actions in many animal disease models and in vitro at picomolar to nanomolar concentrations is summarized in Tables 1 and 2. SPMs have proven to impact disease models, encompassing infection (bacterial and viral) [33], sepsis [34,35], lupus [36], vascular [37,38], airway [39,40], dermal [41], ocular [42], pain [43,44], fibrosis [45], tissue healing [46], and cancer [47]. Reduced SPM levels are identified in the peripheral blood of patients with sepsis [48,49], SARS-COV2 [50,51], lupus [52], ischemic stroke [53], cystic fibrosis [54,55], allergic lung inflammation [56 & ] and Alzheimer's disease [57].…”

Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries

“… 25 , 26 Treatment with 17R-RvD1 was associated with reduced VSMC migration through cyclic adenosine monophosphate and protein kinase A pathways, 27 and both 17R-RvD1 and benzo-RvD1 decreased NIH in a rat model with topical gel application. 28 We further described a poly-lactic-co-glycolic acid (PLGA)-based film device with unidirectional release of RvD1, which achieved good SPM delivery and reduced NIH, but this approach is limited to an open surgical environment. 24 The present work investigates a carrier with potential for catheter-based applications.…”