GDF11 Alleviates Neointimal Hyperplasia in Rat Artery Injury Model Via Regulating Endothelial NLRP3-Inflammasome Activation and Rapid Re-Endothelialization

Background: Neointimal hyperplasia induced by interventional surgery can lead to progressive obliteration of the vascular lumen, which has become a major factor affecting prognosis. It is commonly accepted that the rate of re-endothelialization is inversely related to neointima formation. Growth differentiation factor 11 (GDF11) is a secreted protein with anti-inflammatory, antioxidant, and anti-aging properties. Recent reports indicate that GDF11 can improve vascular remodeling by maintaining differentiated phenotypes for vascular smooth muscle cells. However, it is not known whether and how GDF11 acts to promote re-endothelialization in vascular injury. The present study was performed to clarify the influence of GDF11 on re-endothelialization after vascular injury. Methods An adult Sprague-Dawley rat model of common-carotid-artery balloon-dilatation injury was surgically established. A recombinant adenovirus carrying GDF11 was delivered into the common carotid artery to overexpress GDF11. Vascular re-endothelialization and neointima formation were carried out on harvested carotid arteries through histomolecular analysis. CCK8 analysis, LDH release and western blotting were performed to investigate the effects of GDF11 on endothelial NLRP3-inflammasome activation and relevant signaling pathways in vitro. Results GDF11 significantly enhanced re-endothelialization and reduced neointima formation in rats with balloon-dilatation injury by suppressing the activation of the NLRP3 inflammasome. Endoplasmic-reticulum stress (ER stress) inhibitor, 4PBA administration attenuated endothelial NLRP3-inflammasome activation induced by Lysophosphatidylcholine. Besides, up-regulation of LOX1 expression involved elevated endoplasmic-reticulum stress, and could result in endothelial NLRP3-inflammasome activation. Moreover, GDF11 significantly inhibited NLRP3-inflammasome-mediated endothelial cell pyroptosis through the negative regulation of LOX-1-dependent ER stress. Conclusions We conclude that GDF11 improves re-endothelialization and can attenuate vascular remodeling by reducing endothelial NLRP3-inflammasome activation. These findings shed light on new treatment strategies to promote re-endothelialization based on GDF11 as a future target.