Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

Abstract

Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized proresolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.

Protective Effects of ω-3 PUFA in Anthracycline-Induced Cardiotoxicity: A Critical Review

“…Moreover, the ω-3 modulatory action on l -type calcium channels may result in reduced cytosolic free Ca 2+ and Ca 2+ influx rate, which is believed to prevent the cytosolic calcium overload taking place during the ischemic insult [ 36 ]. The anti-inflammatory and anti-thrombotic effects of ω-3 PUFA have mainly been related to their metabolic conversion to oxygenated derivatives, which are broadly named oxylipins, and are highly bioactive factors acting at very low concentrations [ 37 , 38 ]. Following a stimulus, both the LC-ω-3 PUFA EPA and DHA or the ω-6 PUFA arachidonic acid (AA), are released from cell membranes and converted to oxylipins with similar structures, but often contrasting effects.…”

Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model

“…Recent investigations suggest that the evolving pharmacobiology of resolution may offer new candidate vascular therapeutics. 34 SPMs are naturally occurring autacoids and exert homeostatic effects across a range of disease models with biologic activity in picomolar to nanomolar concentrations. 10 In this study, we found that RvD1 delivered to the external surface of rabbit vein grafts at the time of implantation through either a Pluronic gel or a PLGA film reduced neointimal hyperplasia at 28 days by 50% to 61% compared with bypass-only controls.…”

“…Recent work has described biosynthetic pathways of SPMs in vascular tissues, signaling mechanisms, and vascular cell-specific responses to various SPMs. 34,38,41 Definition of a “resolution index” biomarker after acute vascular injury, similar to that employed in other models of sterile inflammation (eg, peritonitis), could also be useful as a surrogate end point for translational studies. 13,42,43 Along these lines, we observed an increase in the ratio of RvD1 to the proinflammatory lipid mediator LTB 4 in vein grafts treated with RvD1-loaded films.…”

Oxymatrine suppresses MOVAS proliferation induced by platelet-derived growth factor via G0/G1 arrest

“…After vascular injury, a variety of growth factors, cytokines and chemokines are synthesized and secreted, which can stimulate VSMCs phenotype switching, accelerate VSMCs migration to inner membranes, induce the excessive proliferation of VSMCs and further lead to vascular restenosis [34][35][36]. PDGF, mainly expressed in VSMCs and endothelial cells, promote mitosis and play an important role in the proliferation of VSMCs [6][7][8]37].…”