Details

Autor(en) / Beteiligte

• Aw, Wen Yih
• Cho, Crescentia
• Wang, Hao
• Cooper, Anne Hope
• Doherty, Elizabeth L
• Rocco, David
• Huang, Stephanie A
• Kubik, Sarah
• Whitworth, Chloe P
• Armstrong, Ryan
• Hickey, Anthony J
• Griffith, Boyce
• Kutys, Matthew L
• Blatt, Julie
• Polacheck, William J

Titel

Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation

Ist Teil von

• Science advances, 2023-02, Vol.9 (7), p.eade8939

Ort / Verlag

United States: American Association for the Advancement of Science

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Somatic activating mutations of are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of -driven VMs consisting of human umbilical vein endothelial cells expressing activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in -driven VMs.