Search

Cerebral aneurysm growth is characterized by vessel wall frailness, although the underlying cellular mechanisms are unclear. Here, we examined the relationship between inflammatory smooth muscle cells (SMCs) and endothelial cells (ECs) in cerebral aneurysms, including the mechanisms underlying inflammatory SMC-induced changes in ECs. Five saccular cerebral aneurysms were collected and five temporal artery samples were used as controls. Cells and cytokines were detected by immunohistochemistry and TUNEL (transferase dUTP nick end labeling) assays performed to evaluate apoptosis. Human umbilical vein endothelial cells (HUVECs) were seeded on collagen I, IV, and VI-coated plates for cell adhesion assays and inflammatory SMCs (iSMCs) were established by culture in flexible silicone chambers subjected to cyclic mechanical stretch. HUVECs were cultured in iSMC-conditioned medium, followed by evaluation of their viability, apoptosis, and function, and determination of VEGF (vascular endothelial growth factor) -A and integrin levels by western blotting. Aneurysm tissue contained fewer SMCs and lacked ECs. In aneurysm walls, more matrix metalloproteinase (MMP) -1, MMP-3, and apoptotic cells were detected, accompanied by decreased collagen IV and VI levels. Cell adhesion assays revealed that more HUVECs were attached in collagen IV and VI-coated plates compared with controls. iSMC-conditioned medium significantly reduced HUVEC viability and apoptosis showed an increased trend; however, the difference was not significant. iSMC medium also reduced tube formation and migration of HUVECs. Moreover, iSMC medium reduced HUVEC expression of VEGF-A, integrin α1, integrin α2, and integrin β. Our data demonstrate a lack of SMCs and ECs in aneurysm walls, accompanied by elevated MMP and decreased collagen levels. In vitroassays showed that iSMCs induced reduction in EC adhesion, and caused EC dysfunction. Understanding of the relationships among SMC, EC, and collagens during aneurysm progression provides an additional therapeutic option for prevention of cerebral aneurysm progression.

This study explored a new rosuvastatin calcium- and heparin-loaded poly(l-lactide-co-caprolactone) (PLCL) scaffold for covered stents for treating aneurysms. The mechanism of rosuvastatin-induced endothelialization via vascular endothelial growth factor (VEGF)-A elevation was further explored. Rosu50, Rosu75, Rosu100, and phosphate-buffered saline (PBS) nanofibrous scaffolds were fabricated by coaxial electrospinning and observed by electron microscopy. Anticoagulation and pro-endothelialization properties were tested. Sixteen rabbits were selected for an in vivo assay and underwent microsurgery to establish a carotid aneurysm model. The animals were treated with covered stents and followed for 4 months using digital subtraction angiography (DSA), electron microscopy, and histology. Rosuvastatin-treated human umbilical vein endothelial cell (HUVEC) viability, function, and VEGF-A modulation were further studied to elucidate the pro-endothelialization mechanism of rosuvastatin. Our study demonstrates that rosuvastatin and heparin can be incorporated into PLCL nanofibers via electrospinning. Rosu100 nanofiber scaffolds exhibited significant anticoagulation properties. The viability of HUVECs transferred to Rosu100 nanofiber scaffolds was increased significantly. In vivo, DSA revealed that the Rosu100 group had better outcomes than the PBS group. In addition, the Rosu100 stents induced more integrated endothelialization. Further study demonstrated that rosuvastatin promoted HUVEC viability and function in vitro. The effects of rosuvastatin may be attributed to an elevation in VEGF-A. We demonstrated that rosuvastatin- and heparin-loaded PLCL-covered stents show favorable anticoagulation and pro-endothelialization properties in vitro and in vivo in a rabbit aneurysm model. VEGF-A elevation played a crucial role in rosuvastatin-promoted endothelialization. This work provides an additional option for treating cerebral aneurysms with covered stents.

Supplemental Digital Content is available in the text.

This study explored a new approach to enhance aneurysm (AN) neck endothelialization via erythropoietin (EPO)‐induced endothelial progenitor cell (EPC) stimulation. Results suggest that EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via vascular endothelial growth factor modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. This study explored a new approach to enhance aneurysm (AN) neck endothelialization via erythropoietin (EPO)‐induced endothelial progenitor cell (EPC) stimulation. Results suggest that EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via vascular endothelial growth factor modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. Endovascular coil embolization is an attractive therapy for cerebral ANs, but recurrence is a main problem affecting long‐term outcomes. In this study, we explored a new approach to enhance AN neck endothelialization via EPO‐induced EPC stimulation. Ninety adult male Sprague‐Dawley rats were selected for an in vivo assay, and 60 of them underwent microsurgery to create a coiled embolization AN model. The animals were treated with EPO, and endothelial repair was assessed via flow cytometry, immunofluorescence, electronic microscopy, cytokine detection, and routine blood work. EPO improved the viability, migration, cytokine modulation, and gene expression of bone marrow‐derived EPCs and the results showed that EPO increased the number of circulating EPCs and improved endothelialization compared with untreated rats (p< .05). EPO had no significant effect on the routine blood work parameters. In addition, the immunofluorescence analysis showed that the number of KDR+cells in the AN neck was elevated in the EPO‐treated group (p< .05). Further study demonstrated that EPO promoted EPC viability and migration in vitro. The effects of EPO may be attributed to the modulation of vascular endothelial growth factor (VEGF). In particular, EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via VEGF modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. Erythropoietin (EPO) is involved in erythropoiesis and related conditions and is reported to enhance stem‐cell mobilization from bone marrow while elevating stem‐cell viability and function. In this study, EPO was also found to stimulate endothelial progenitor cells to induce the endothelialization of a coiled embolic aneurysm neck via vascular endothelial growth factor modulation. Endothelialization induction provides an additional therapeutic opportunity during vascular inner layer repair and remodeling. The results provide important information on the unique role EPO plays during vascular repair and remodeling.