10 Additionally, endothelial ROBO4 mutation or deficiency in mice results in TAA formation with a bicuspid aortic valve. For example, the endothelial angiotensin type 1 receptor is responsible for aneurysm formation in Fbn1 mgR/mgR mice, 9 while endothelial ADAM17 contributes to elastase‐induced TAAs by disrupting endothelial junctions. ![]() 7, 8 More recently, the contribution of vascular endothelial cells (ECs) has been reported as a crucial factor in TAA pathogenesis. 5, 6 On this basis, therapeutic strategies targeting SMCs with angiotensin type 1 receptors have been developed however, their efficacy over conventional medications (eg, β‐blockers) has not been confirmed in human patients. 3, 4 Mutations in extracellular matrix (ECM) proteins and SMC contractile proteins are also related to the development of TAAs. 2 TAAs can be associated with heritable diseases with syndromic features, (eg, Marfan syndrome and Loeys‐Dietz syndrome) and exhibit the marked activation of transforming growth factor β (TGF‐β) and mitogen‐activated protein kinase signaling in vascular smooth muscle cells (SMCs). 1 Surgical resection or stent graft insertion is commonly performed as a prophylactic measure against aortic rupture however, effective medications to halt or reverse TAA progression have yet to be established. TAAs typically progress asymptomatically and can be life‐threatening when they rupture or dissect. Thoracic aortic aneurysm (TAA) refers to an irreversible enlargement of the aortic wall that exceeds 1.5 times the normal aortic diameter. Nonstandard Abbreviations and Acronyms α‐SMA Furthermore, RNA sequencing and immunostaining of the aortic valve revealed the upregulation of genes involved in endothelial‐to‐mesenchymal transition, inflammatory response, and tissue fibrosis in DKO valves and the presence of activated valve interstitial cells. DKO mice also showed progressive aortic valve thickening with collagen deposition from postnatal day 14, as well as turbulent flow in the ascending aorta. DKO mice showed the exacerbation of thoracic aortic aneurysms when compared with those of SMKO and upregulated Thbs1, a mechanical stress–responsive molecule, throughout the aorta. Knockdown of FBLN4 in human aortic ECs induced mesenchymal cell–like changes with the upregulation of mesenchymal genes, including TAGLN and MYL9. An evaluation of the thoracic aortic aneurysm phenotype and screening of altered signaling pathways were performed. ![]() Fbln4 double knockout ( DKO) mice in ECs and smooth muscle cells were generated and subjected to histological analysis, echocardiography, Western blotting, RNA sequencing, and immunostaining. Gene silencing of FBLN4 was conducted on human aortic ECs to evaluate morphological changes and gene expression profile. Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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