Cerebral cavernous malformations (CCMs) are irregularly shaped blood vessels that mainly occur in the central nervous system and can progress to fatal brain hemorrhage. Recent studies in mice revealed that changes in the extracellular matrix (ECM) play a significant role in CCM disease progression, but modeling these changes in ECM composition remains a challenge. Yordanov and Keyser et al. developed a 3D model to grow CCM vessels in distinct extracellular matrices, enabling an understanding down to the single-cell level.

The study builds on a previous 3D micro-vessel model, published by the team’s collaborator Christopher Chen. The authors adapted this model to simulate the growth of CCMs in the human extracellular matrix. They then used immunofluorescence analysis to measure changes in CCM pathology and verified the integrity of their blood vessels with leakage assays.

The team showed their model successfully replicates the hallmarks of CCM disease. They demonstrated that genes responsible for hyaluronic acid, a main central nervous system ECM component, are differentially expressed. By restoring certain types of hyaluronic acid to their modeled ECM, they showed CCM disease can be inhibited or slowed.

“Our study further provides a proof-of-principle of the effectiveness of 3D micro-vessel modeling in examining the role of ECM components in vascular disease,” said author Mikaela Keyser. “This approach will apply to research aimed to investigate similar non-cell autonomous mechanisms in other vascular malformations and diseases, such as lymphatic malformations and aneurysms.”

The authors say their study forms a solid foundation for further studies on the relationship between hyaluronic acid and CCM pathogenesis, potentially leading to new therapies to dampen progressive CCM disease.

Source: “Hyaluronic acid turnover controls the severity of cerebral cavernous malformations in bioengineered human micro-vessels,” by Teodor E. Yordanov, Mikaela S. Keyser, Marco A. Enriquez Martinez, Tyron Esposito, Juliann B. Tefft, Elysse K. Morris, Larisa I. Labzin, Samantha J. Stehbens, Alan E. Rowan, Benjamin M. Hogan, Christopher S. Chen, Jan Lauko, and Anne K. Lagendijk, APL Bioengineering (2024). The article can be accessed at https://doi.org/10.1063/5.0159330.