10.8 - AT1R blockade together with AT2R stimulation prevents aortic aneurysm in mice with progressively severe Marfan syndrome

Keiichi Asano (Icahn School of Medicine at Mount Sinai), Anna Cantalupo (Icahn School of Medicine at Mount Sinai), Jens Hansen (Icahn School of Medicine at Mount Sinai), Bart Spronck (Yale University), Jay Humphrey (Yale University), Ravi Iyengar (Icahn School of Medicine at Mount Sinai), Francesco Ramirez (Icahn School of Medicine at Mount Sinai)

Angiotensin II receptor signaling regulate vascular tone by stimulating either vasoconstriction (AT1R) or vasodilation (AT2R). AT1R antagonism (via losartan) has been shown to mitigate thoracic aortic aneurysm (TAA) progression in mouse models of Marfan syndrome (MFS). Here we monitored multiple pathological readouts of TAA in MFS mice chronically treated for 90 days with either losartan, the AT2R agonist C21, or both. While C21 had no apparent effects on arterial disease by itself, it significantly enhanced losartan’s efficacy by preventing death of MFS mice from ruptured TAA during the treatment period. Specifically, the combination therapy normalized the diameters of the aortic root and ascending aorta, the architecture of the vessel wall, endothelial-dependent relaxation, and circumferential wall strength (a strong biomechanical indicator of aneurysmal vulnerability). Computational analyses of bulk RNASeq data predicted that the combination therapy largely decreased expression of abnormally upregulated genes, principally those associated with inflammatory pathways. By contrast, these in silico analyses predicted no modifications of signaling pathways associated with dysregulated mitochondrial energy metabolism. Ongoing investigations are using single cell RNASeq to identify the different cell types targeted by the two drugs used in combination therapy, as well as potential cell-cell interactions that underlie the efficacy of the combination therapy.