A Pulsatile Flow System to Engineer Aneurysm and Atherosclerosis Mimetic Extracellular Matrix

Area of Science:

• Biomedical Engineering
• Vascular Biology
• Tissue Engineering

Background:

• Blood flow alterations are linked to arterial diseases like atherosclerosis and aneurysm.
• Understanding flow-induced changes in vascular tissue is crucial for disease modeling and treatment.

Purpose of the Study:

• To develop a novel flow device to study flow-induced vascular tissue remodeling.
• To investigate the impact of different flow conditions on extracellular matrix (ECM) composition.
• To explore the role of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in flow-induced ECM changes.

Main Methods:

• A miniaturized, pumpless, close-loop flow device was used to expose 3D engineered vascular smooth muscle tissues to distinct flow conditions (high-velocity pulsatile vs. low-velocity disturbed).
• Analysis of ECM composition (elastin and collagen I), mRNA levels of ECM components, and gene expression of MMPs and TIMPs.
• Assessment of the effect of doxycycline, an MMP inhibitor, on flow-induced ECM remodeling.

Main Results:

• Two distinct flow regimes were identified, differentially affecting elastin and collagen I assembly.
• Low-velocity disturbed flow promoted collagen assembly while impairing elastin, mimicking disease phenotypes.
• Flow-dependent differential gene expression of MMPs and TIMPs, not ECM mRNA levels, drove ECM composition changes.
• Doxycycline treatment inhibited the low-velocity flow-induced ECM remodeling.

Conclusions:

• The developed flow device effectively recapitulates key aspects of flow-induced vascular tissue morphogenesis.
• MMPs and TIMPs are key mediators of flow-induced ECM remodeling in vascular tissues.
• This platform can be utilized for drug efficacy studies in vascular diseases, providing mechanistic insights into therapeutic interventions.