Protective Role of Endothelial Fibulin‐4 in Valvulo‐Arterial Integrity


 
 
 Homeostasis of the vessel wall is cooperatively maintained by endothelial cells (ECs), smooth muscle cells, and adventitial fibroblasts. The genetic deletion of fibulin‐4 (
 Fbln4
 ) in smooth muscle cells (
 SMKO
 ) leads to the formation of thoracic aortic aneurysms with the disruption of elastic fibers. Although
 Fbln4
 is expressed in the entire vessel wall, its function in ECs and relevance to the maintenance of valvulo‐arterial integrity are not fully understood.
 
 
 
 
 
 Gene silencing of
 FBLN4
 was conducted on human aortic ECs to evaluate morphological changes and gene expression profile.
 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. An evaluation of the thoracic aortic aneurysm phenotype and screening of altered signaling pathways were performed. Knockdown of
 FBLN4
 in human aortic ECs induced mesenchymal cell–like changes with the upregulation of mesenchymal genes, including
 TAGLN
 and
 MYL9
 .
 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.
 DKO
 mice also showed progressive aortic valve thickening with collagen deposition from postnatal day 14, as well as turbulent flow in the ascending aorta. 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.
 
 
 
 
 The current study uncovers the pivotal role of endothelial fibulin‐4 in the maintenance of valvulo‐arterial integrity, which influences thoracic aortic aneurysm progression.
