Hyaluronic acid turnover controls the severity of cerebral cavernous malformations in bioengineered human micro-vessels

Yordanov, TE; Keyser, MS; Enriquez Martinez, MA; Esposito, T; Tefft, JB; Morris, EK; Labzin, LI; Stehbens, SJ; Rowan, AE; Hogan, BM; Chen, CS; Lauko, J; Lagendijk, AK

Author(s): Yordanov, TE; Keyser, MS; Enriquez Martinez, MA; Esposito, T; Tefft, JB; Morris, EK; Labzin, LI; Stehbens, SJ; Rowan, AE; Hogan, BM; Chen, CS; Lauko, J; Lagendijk, AK;
Details: Publication Year 2024,Volume 8,Issue #1,Page 016108
Journal Title: APL Bioengineering
Publication Type: Research article
Abstract: Cerebral cavernous malformations (CCMs) are vascular lesions that predominantly form in blood vessels of the central nervous system upon loss of the CCM multimeric protein complex. The endothelial cells within CCM lesions are characterized by overactive MEKK3 kinase and KLF2/4 transcription factor signaling, leading to pathological changes such as increased endothelial cell spreading and reduced junctional integrity. Concomitant to aberrant endothelial cell signaling, non-autonomous signals from the extracellular matrix (ECM) have also been implicated in CCM lesion growth and these factors might explain why CCM lesions mainly develop in the central nervous system. Here, we adapted a three-dimensional microfluidic system to examine CCM1 deficient human micro-vessels in distinctive extracellular matrices. We validate that pathological hallmarks are maintained in this model. We further show that key genes responsible for homeostasis of hyaluronic acid, a major extracellular matrix component of the central nervous system, are dysregulated in CCM. Supplementing the matrix in our model with distinct forms of hyaluronic acid inhibits pathological cell spreading and rescues barrier function. Hyaluronic acid acts by dampening cell-matrix adhesion signaling in CCM, either downstream or in parallel of KLF2/4. This study provides a proof-of-principle that ECM embedded 3D microfluidic models are ideally suited to identify how changes in ECM structure and signaling impact vascular malformations.
Department(s): Laboratory Research
PubMed ID: 38352162
Publisher's Version: https://doi.org/10.1063/5.0159330
Open Access at Publisher's Site: https://doi.org/10.1063/5.0159330
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-20 06:18:07

Last Modified: 2024-08-20 06:56:39