Cyclic Mechanical Stretch Induced Smooth Muscle Cell Changes in Cerebral Aneurysm Progress by Reducing Collagen Type IV and Collagen Type VI Levels

Abstract

Background/Aims: Cerebral aneurysm growth is characterized by continuous structural weakness of local smooth muscle cells, though the mechanism is unclear. In this study, we examine protein changes in cerebral aneurysm and human brain vascular smooth muscle cells after cyclic mechanical stretch. We further explore the relationship between the smooth muscle cell changes and reductions in the levels of collagen types IV and VI. Methods: Saccular cerebral aneurysms (n=10) were collected, and temporal artery samples were used as controls. Quantitative proteomics were analyzed and histopathological changes were examined. Smooth muscle cells were cultured in a flexible silicone chamber and subjected to 15% cyclic mechanical stretch. The effect of stretch on the cell viability, function, gene and protein expression were further studied for the understanding the molecular mechanism of aneurysm development. Results: Proteomics analysis revealed 92 proteins with increased expression and 88 proteins with decreased expression compared to the controls (p<0.05). KEGG pathway analysis showed that the change in focal adhesion and extracellular matrix-receptor interaction, suggesting the involvement of collagen type IV and VI. The aneurysm tissue exhibited fewer smooth muscle cells and lower levels of collagen type IV and VI. Human brain vascular smooth muscle cell culture showed spindle-like cells and obvious smooth muscle cell layer. Cell proteomics analysis showed that decreased expression of 118 proteins and increased expression of 32 proteins in smooth muscle cells after cyclic mechanical stretch. KEGG pathway analysis indicated that focal adhesion and ECM-receptor interaction were involved. After cyclic mechanical stretch, collagen type IV and IV expression were decreased. Moreover, the stretch induced MMP-1 and MMP-3 expression elevation. Conclusion: We demonstrated that collagen type IV and VI were decreased in cerebral aneurysms and continuous cyclic mechanical stretch induced smooth muscle cell changes. Smooth muscle cell protection provides an additional therapeutic option to prevent the growth of cerebral aneurysms.

Comparative bioinformatics analysis between proteomes of rabbit aneurysm model and human intracranial aneurysm with label‐free quantitative proteomics

“…Among these 180 proteins, 88 were significantly up‐regulated, and 92 were down‐regulated in the IA group compared to the STA group. The results were shown in our previous studies 16,17 …”

“…Collagen type IV, another essential protein present in SMCs that can stimulate the ‐SMA and SM‐MHC promoters, 42 has been previously verified by us to be crucial in focal adhesion and ECM pathways. We found that human IA tissues had fewer SMCs and less collagen type IV 16 . We also found that CAV‐1 is a ubiquitous gene that appears in almost every study of the rabbit aneurysm model.…”

Inflammatory Smooth Muscle Cells Induce Endothelial Cell Alterations to Influence Cerebral Aneurysm Progression via Regulation of Integrin and VEGF Expression

“…Degeneration of the ECM is primarily induced by secretion of inflammatory cytokines and cell infiltration 19 –21 . Our previous comparative proteomic analysis demonstrated that collagen IV and VI levels were reduced in comparisons of aneurysm and STA tissues 22 . In this study, we observed that levels of collagen IV and VI were clearly decreased in the aneurysm wall by IHC.…”

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

“…Several inflammatory mediators are triggered and then release large amounts of inflammatory cytokines and oxidative factors. This can cause a number of pathological processes including disruption of internal elastic laminate, vascular smooth muscle cell (VSMC) phenotype modulation, and dysfunctional extracellular matrix (ECM) remodeling [2–4]. When vessel walls degenerate, intracranial arteries become too weak to resist the blood dynamic force, and pouch-like dilatations of cerebral arteries occur.…”