Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Departments of Medicine and Bioengineering, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
FASEB J. 2023 Jul;37(7):e23029. doi: 10.1096/fj.202201745RR.
The increasing incidence of cardiovascular disease (CVD) has led to a significant ongoing need to address this surgically through coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). From this, there continues to be a substantial burden of mortality and morbidity due to complications arising from endothelial damage, resulting in restenosis. Whilst mast cells (MC) have been shown to have a causative role in atherosclerosis and other vascular diseases, including restenosis due to vein engraftment; here, we demonstrate their rapid response to arterial wire injury, recapitulating the endothelial damage seen in PCI procedures. Using wild-type mice, we demonstrate accumulation of MC in the femoral artery post-acute wire injury, with rapid activation and degranulation, resulting in neointimal hyperplasia, which was not observed in MC-deficient Kit mice. Furthermore, neutrophils, macrophages, and T cells were abundant in the wild-type mice area of injury but reduced in the Kit mice. Following bone-marrow-derived MC (BMMC) transplantation into Kit mice, not only was the neointimal hyperplasia induced, but the neutrophil, macrophage, and T-cell populations were also present in these transplanted mice. To demonstrate the utility of MC as a target for therapy, we administered the MC stabilizing drug, disodium cromoglycate (DSCG) immediately following arterial injury and were able to show a reduction in neointimal hyperplasia in wild-type mice. These studies suggest a critical role for MC in inducing the conditions and coordinating the detrimental inflammatory response seen post-endothelial injury in arteries undergoing revascularization procedures, and by targeting the rapid MC degranulation immediately post-surgery with DSCG, this restenosis may become a preventable clinical complication.
心血管疾病（CVD）发病率的不断增加，导致通过冠状动脉旁路移植术（CABG）和经皮冠状动脉介入治疗（PCI）来解决这一问题的需求持续存在。由此，由于内皮损伤导致的并发症，包括静脉移植后的再狭窄，导致死亡率和发病率仍然很高。虽然肥大细胞（MC）已被证明在动脉粥样硬化和其他血管疾病中具有致病作用，包括再狭窄；在这里，我们证明了它们对动脉线损伤的快速反应，再现了 PCI 手术中观察到的内皮损伤。使用野生型小鼠，我们证明了 MC 在股动脉急性线损伤后积累，迅速激活和脱颗粒，导致内膜增生，而在 MC 缺陷型 Kit 小鼠中未观察到这种情况。此外，中性粒细胞、巨噬细胞和 T 细胞在野生型小鼠损伤区域丰富，但在 Kit 小鼠中减少。在将骨髓来源的 MC（BMMC）移植到 Kit 小鼠后，不仅诱导了内膜增生，而且中性粒细胞、巨噬细胞和 T 细胞群体也存在于这些移植的小鼠中。为了证明 MC 作为治疗靶点的实用性，我们在动脉损伤后立即给予 MC 稳定药物二钠色甘酸钠（DSCG），并能够显示出野生型小鼠中内膜增生减少。这些研究表明，MC 在诱导动脉再血管化过程中内皮损伤后出现的条件和协调有害炎症反应方面具有关键作用，并且通过 DSCG 立即靶向手术后的快速 MC 脱颗粒，这种再狭窄可能成为可预防的临床并发症。
