Abstract 251: Selective Deletion of Smad4 in Smooth Muscle Cells Causes Thoracic Aortic Aneurysm in Mice

TGFβ signaling have been implicated in the onset of thoracic aortic aneurysms (TAA). Recently, it has been described that mutations in SMAD4, an intracellular transducer required in the TGFβ canonical pathway, present aortic disease in humans. Although transgenic models recapitulating mutations of TGFβ pathway have been studied, Smad4 role in the onset of TAA has never been explored. Smad4 homozygotes mice are embryonically lethal, thus, we postnatally targeted the gene, using a tamoxifen (TAM)-inducible Cre recombinase under the smooth muscle myosin heavy chain promoter. Activation by TAM suppressed Smad4 in aorta SMCs of Smadf/f;Myh11-CreERT2 mice. We found that, most of these mice died 4/6 months later from hemothorax due to rupture of thoracic aorta, while untreated mice survived. Echocardiography showed a progressive dilation of aorta and TAA formation. Histology revealed progressive fragmentation of elastic lamellae with increased inflammatory infiltrates at sites of disarrangement, rich in macropha...