Spatio-temporal model of Meox1 expression control involvement of Sca-1-positive stem cells in neointima formation through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4

Abstract Aims Neointimal 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 results Aneointimal 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. Conclusions Spatio-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.