Abstract
BackgroundNeointimal hyperplasia induced by interventional surgery can lead to progressive obliteration of the vascular lumen, which has become a major factor affecting prognosis. The rate of re-endothelialization is known to be inversely related to neointima formation. Growth differentiation factor 11 (GDF11) is a secreted protein with anti-inflammatory, antioxidant, and antiaging properties. Recent reports have indicated that GDF11 can improve vascular remodeling by maintaining the differentiated phenotypes of vascular smooth muscle cells. However, it is not known whether and how GDF11 promotes re-endothelialization in vascular injury. The present study was performed to clarify the influence of GDF11 on re-endothelialization after vascular injury.MethodsAn 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 assessed in harvested carotid arteries through histomolecular analysis. CCK-8 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.ResultsGDF11 significantly enhanced re-endothelialization and reduced neointima formation in rats with balloon-dilatation injury by suppressing the activation of the NLRP3 inflammasome. Administration of an endoplasmic reticulum stress (ER stress) inhibitor, 4PBA, attenuated endothelial NLRP3 inflammasome activation induced by lysophosphatidylcholine. In addition, upregulation of LOX-1 expression involved elevated ER stress and could result in endothelial NLRP3 inflammasome activation. Moreover, GDF11 significantly inhibited NLRP3 inflammasome-mediated endothelial cell pyroptosis by negatively regulating LOX-1-dependent ER stress.ConclusionsWe 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.
Highlights
Neointimal hyperplasia induced by interventional surgery can lead to progressive obliteration of the vascular lumen, which has become a major factor affecting prognosis
Growth differentiation factor 11 (GDF11) inhibited NLRP3 inflammasome activation and pyroptosis in lysoPC‐treated human endothelial cells To test the cytotoxicity induced by lysoPC in human endothelial cells, we determined cell viability and LDH release
LysoPC concentration-dependently inhibited the expression of GDF11 in human endothelial cells, suggesting that GDF11 may affect the viability of lysoPC-exposed human endothelial cells (Fig. 1C, D)
Summary
Neointimal hyperplasia induced by interventional surgery can lead to progressive obliteration of the vascular lumen, which has become a major factor affecting prognosis. The rate of re-endothelialization is known to be inversely related to neointima formation. Recent reports have indicated that GDF11 can improve vascular remodeling by maintaining the differentiated phenotypes of vascular smooth muscle cells. It is not known whether and how GDF11 promotes re-endothelialization in vascular injury. Percutaneous intracavitary interventional therapy is minimally invasive and has a definite curative effect. This procedure is currently an important treatment technique for cardiovascular diseases and is widely used in clinics. Intimal neoplasia induced by interventional surgery can lead to restenosis, which has become a major factor affecting prognosis [2]. Promoting the re-endothelialization of injured blood vessels is urgently needed to reduce delayed restenosis and improve patients’ quality of life after interventional surgery
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