Induced Elastin Regeneration by Chronically Activated Smooth Muscle Cells for Targeted Aneurysm Repair

Document Type


Publication Date


Publication Title

Acta Biomaterialia


Elastin breakdown in vascular aneurysms is mediated by cytokines such as tumor necrosis factor α (TNF-α, which induces vascular smooth muscle cell (SMC) activation and regulates their deposition of matrix. We previously demonstrated that exogenous supplementation with TGF-β1 (1 ng ml-1) and hyaluronan oligomers (0.786 kDa, 0.2 μg ml-1) cues the upregulation of elastin matrix synthesis by healthy cultured SMCs. Here, we determine whether these cues likewise enhance elastin matrix synthesis and assembly by TNF-α-stimulated SMCs, while restoring their healthy phenotype. Adult rat aortic SMCs were treated with TNF-α alone or together with TGF-β1/hyaluronan oligomeric cues and the release of inflammatory markers were monitored during over a 21 day culture. Biochemical analysis was used to quantify cell proliferation, matrix protein synthesis and cross-linking efficiency, while immunofluorescence and electron microscopy were used to analyze the elastin matrix quality. It was observed that SMC activation with TNF-α (10 ng ml-1) induced matrix calcification and promoted production of elastolytic MMP-2 and MMP-9. However, these effects were attenuated by the addition of TGF-β1 and HA oligomer cues to TNF-α-stimulated cultures, which also enhanced tropoelastin and collagen production, improved elastin matrix yield and cross-linking, promoted elastin fiber formation and suppressed elastase activity, although the release of MMP-2 and MMP-9 was not affected. Overall, the results suggest that TGF-β1 and HA oligomers are potentially useful in suppressing SMC activation and inducing regenerative elastin repair within aneurysms. © 2009 Acta Materialia Inc.