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

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 pro-resolving 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.

Biosynthesis of proresolving lipid mediators by vascular cells and tissues.

Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA ex vivo produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. Addition of 17-HDHA to human arteries similarly increased resolvin production. Primary cultures of human saphenous vein endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) converted 17-HDHA to SPMs, including resolvin D1 (RvD1) and other D-series resolvins and protectins. This was accompanied by a rapid translocation of 5-LOX from nucleus to cytoplasm in both ECs and VSMCs, potentially facilitating SPM biosynthesis. Conditioned medium from cells exposed to 17-HDHA inhibited monocyte adhesion to TNF-α-stimulated EC monolayers. These downstream effects were partially reversed by antibodies against the RvD1 receptors ALX/FPR2 and GPR32. These results suggest that autocrine and/or paracrine signaling via locally generated SPMs in the vasculature may represent a novel homeostatic mechanism of relevance to vascular health and disease.-Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Biosynthesis of proresolving lipid mediators by vascular cells and tissues.