Abstract 222: D-Series Resolvins Modulate Postinjury Signaling Pathways in Vascular Smooth Muscle Cells
Introduction: Recent work suggests that the resolution of inflammation is an active process involving specialized molecules that are locally generated. D-series resolvins (RvD) are endogenous pro-resolving lipid mediators derived from the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA). VSMC activation following vascular injury leads to neointimal hyperplasia which may reflect a relative “resolution deficit” in the vessel wall.
Objectives: We sought to determine the effects of RvD on injury-related inflammatory and growth factor signaling pathways in VSMC, using in vitro and in vivo models.
Hypothesis: We hypothesize that RvD will attenuate VSMC activation responses and modulate vascular injury.
Methods: Human VSMC were treated with cytokines (TNF-α, IL-1β), growth factors (PDGF, AngII) or oxidant stress (H2O2) in the presence of RvD1 or RvD2 (.01-100 nM), and phenotype was assessed by cytotoxicity, proliferation, migration (transwell), monocyte adhesion (U937) and adhesion molecule expression (qPCR and flow cytometry) assays. NZW rabbits (N=4) underwent bilateral femoral balloon injury with intraluminal delivery of RvD2 (10 nM vs vehicle control) to examine acute effects (3 days) on the injury response.
Results: RvD treatment of VSMC produced dose-dependent inhibition of VSMC proliferation (max %inhibition: RvD1 58.8%, p<0.01, RvD2 63.1%, p<0.01), migration (RvD1 66.1%, p<0.01%, RvD2 68.8%, p<0.01), monocyte adhesion (RvD1 36.0%, p<0.01, RvD2 41.0%, p<0.01), and inducible adhesion molecule expression (VCAM-1: RvD1 70.5%, p<0.01, RvD2 77.2%, p<0.01; ICAM-1: RvD1 65.4%, p<0.01, RvD2 72.1%, p<0.01) without measurable cytotoxicity. In the rabbit model of balloon arterial injury, proliferation was significantly reduced at 3 days in RvD2 treated vessels (%inhibition 57%, p<0.01).
Conclusion: RvD broadly inhibit VSMC activation responses and may modulate the vascular injury response in-vivo.
- © 2012 by American Heart Association, Inc.