To delineate the effects of integrin av signaling in Marfan syndrome (MFS) and examine the potential efficacy of integrin av blockade as a therapeutic strategy for MFS aneurysms.Induced pluripotent stem cells were differentiated into aortic smooth muscle cells (SMCs) of the second heart field (SHF) and neural crest lineages, enabling in vitro modeling of thoracic aortic aneurysm in MFS. Fbn1C1039G/+ MFS mice treated with integrin av antagonist (GLPG0187) confirmed the pathological role of integrin av on aneurysm formation.Induced pluripotent stem cell-derived MFS SHF SMCs overexpress integrin av relative to MFS neural crest and healthy control SHF cells. Furthermore, downstream targets of integrin av (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity in MFS SHF back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS neural crest and control SMCs, which was then inhibited by GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin av, p-AktThr308, and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6-14 weeks) resulted in reduced aneurysm growth, elastin fragmentation, and normalization of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing.The integrin av-FAK-AktThr308 signaling pathway is activated in induced pluripotent stem cell SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-AktThr308 signaling in Fbn1C1039G/+ mice. Integrin av blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.
View details for DOI 10.1161/ATVBAHA.122.318448
View details for PubMedID 37078287