Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States.
Department of Surgery, University of Virginia, Charlottesville, VA, United States.
Mol Aspects Med. 2017 Dec;58:72-82. doi: 10.1016/j.mam.2017.07.005. Epub 2017 Aug 4.
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.
急性血管损伤发生在许多重要的临床情况下，包括自发性疾病相关事件（如斑块破裂、血栓形成）和治疗干预，如血管成形术、支架置入或旁路手术。内皮细胞（EC）的破坏暴露了下面的基质，导致血小板、凝血蛋白和白细胞迅速沉积。随后会发生血栓炎症反应，其特征是白细胞募集、血管平滑肌细胞（VSMC）激活以及细胞因子、活性氧和生长因子在血管壁内的产生。血管损伤的修复阶段可能会出现白细胞流出、清除碎片和再内皮化。VSMC 的迁移和增殖导致增厚的新生内膜形成，这可能会导致管腔狭窄。随后的重塑涉及基质蛋白的沉积，以及 EC 和 VSMC 恢复到静止状态。最近的研究表明，专门的促解决脂质介质（SPM）调节了这一反应的关键方面，并且可能构成了血管中的一种内源性稳态途径。SPM 对血管细胞直接发挥作用，抵消炎症信号，减少白细胞黏附，并抑制 VSMC 的迁移和增殖。这些作用似乎主要依赖 G 蛋白偶联受体。在一系列血管损伤的动物模型中，包括球囊血管成形术、旁路移植术和实验性动脉瘤形成，SPM 加速修复并减少损伤形成。SPM 的生物活性在 pM-nM 范围内，没有明显的细胞毒性，并且具有广泛的血管保护特性，代表了一类新型的血管治疗药物。本文综述了该领域的当前研究，包括对转化过程中的关键下一步和挑战的考虑。
