👤 Sarah Stassen

Brain arteriovenous malformations (bAVMs) are complex vascular lesions with significant clinical risks. The Hippo signaling pathway, particularly its downstream effector YAP, plays a crucial role in angiogenesis and vascular remodeling. This study investigates the role of YAP and related molecular markers in bAVMs, focusing on the effects of embolization. Immunohistochemical analysis was conducted on tissue samples from bAVM patients (n = 127), as well as on healthy blood vessels (n = 17). YAP, HIF-1α, FGFR1, CTGF, and CYR61 expression were quantified and correlated with clinical parameters. Results: In healthy vessels, YAP exhibited nuclear localization in (sub)endothelial cells and the tunica media, while CTGF and CYR61 were detected in the cytoplasm and extracellular matrix. The expression of YAP, CTGF, and CYR61 was significantly lower in bAVM tissues. Embolized bAVMs exhibited significantly higher expression of YAP, CTGF, and CYR61 compared to non-embolized tissues, suggesting a link between embolization and pro-angiogenic signaling. Additionally, FGFR1 was upregulated in embolized tissues. These results suggest that upregulation of YAP expression via the Hippo pathway might play a key role in bAVM pathophysiology. Embolization may further promote vascular remodeling. Dysregulation of YAP and related molecules in bAVMs warrants further studies to explore potential therapeutic strategies targeting the Hippo pathway. Show less

Hemodynamic forces and Notch signaling are both known as key regulators of arterial remodeling and homeostasis. However, how these two factors integrate in vascular morphogenesis and homeostasis is unclear. Here, we combined experiments and modeling to evaluate the impact of the integration of mechanics and Notch signaling on vascular homeostasis. Vascular smooth muscle cells (VSMCs) were cyclically stretched on flexible membranes, as quantified via video tracking, demonstrating that the expression of Jagged1, Notch3, and target genes was down-regulated with strain. The data were incorporated in a computational framework of Notch signaling in the vascular wall, where the mechanical load was defined by the vascular geometry and blood pressure. Upon increasing wall thickness, the model predicted a switch-type behavior of the Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain transition thickness. These thicknesses varied per investigated arterial location and were in good agreement with human anatomical data, thereby suggesting that the Notch response to hemodynamics plays an important role in the establishment of vascular homeostasis. Show less