Abstract
AimsNeointimal hyperplasia remains a major obstacle in vascular regeneration. Sca-1-positive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle cell (VSMC) and the formation of the intimal lesion. However, the underlying mechanisms during vascular injury are still unknown.Methods and resultsAneointimal formation rat model was prepared by carotid artery injury using 2F-Forgaty. After vascular injury, Meox1 expressions time-dependently increased during the neointima formation, with its levels concurrently increasing in the adventitia, media, and neointima. Meox1 was highly expressed in the adventitia on the first day after vascular injury compared to the expression levels in the media. Conversely, by the 14th day post-injury, Meox1 was extensively expressed more in the media and neointima than the adventitia. Analogous to the change of Meox1 in injured artery, Sca-1+ progenitor cells increased in the adventitia wall in a time-dependent manner and reached peak levels on the 7th day after injury. More importantly, this effect was abolished by Meox1 knockdown with shRNA. The enhanced expression of SDF-1α after vascular injury was associated with the markedly enhanced expression levels of Sca1+ progenitor cell, and these levels were relatively synchronously increased within neointima by the 7th day after vascular injury. These special effects were abolished by the knockdown of Meox1 with shRNA and inhibition of CXCR4 by its inhibitor, AMD3100. Finally, Meox1 concurrently regulated SDF-1α expressions in VSMC via activating CDC42, and CDC42 inhibition abolished these effects by its inhibitor, ZCL278. Also, Meox1 was involved in activation of the CXCR4 expression of Sca-1+ progenitor cells by CDC42.ConclusionsSpatio-temporal model of Meox1 expression regulates theSca-1+progenitor cell migration during the formation of the neointima through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4.
Highlights
Coronary heart diseases are the most prevalent diseases worldwide and the leading cause of death worldwide
drug-eluting stents (DES) has shown superior in preventing in-stent restenosis (ISR), introducing a stent inhibits the proliferation of vascular endothelial cells and smooth muscle cells (SMC) in neointima, resulting in re-endothelialization, which leads to late stent thrombosis (LST) or very-LST (VLST)
Meox1 and Stem cell antigen-1 (Sca-1)+ stem cells are induced during neointimal formation and express spatio-temporal traits during balloon injury-induced artery To identify the expression of Meox1 and Sca-1+ progenitor cells during neointimal formation, we detected the expressions of Sca-1+ and Meox1 at day 1, day 3, day 7, and day 14 after balloon-injured carotid artery
Summary
Coronary heart diseases are the most prevalent diseases worldwide and the leading cause of death worldwide. The introduction of drug-eluting stents (DES) proved to have significant improvement in reducing in-stent restenosis (ISR) incidents and have become the standard use with PCI therapy [1]. DES has shown superior in preventing ISR, introducing a stent inhibits the proliferation of vascular endothelial cells and smooth muscle cells (SMC) in neointima, resulting in re-endothelialization, which leads to late stent thrombosis (LST) or very-LST (VLST). This warrants the need for prolonged use of dual anti-platelet therapy (DAPT), which increases the risk of bleeding and further is an economic burden for patients [2,3,4]. It is urgent to study and understand the underlying mechanisms that drive the pathology restenosis after surgical intervention and explore new target therapy to reduce the physical and economic burden for patients
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