Protective Role of Endothelial Fibulin-4 in Valvulo-Arterial Integrity.
Tram Anh Vu NguyenCaroline Antunes LinoHuynh Thuy HangJuliano Vilela AlvesBui Quoc ThangSeung Jae ShinKaori SugiyamaHiroko MatsunagaHaruko TakeyamaYoshito YamashiroHiromi YanagisawaPublished in: Journal of the American Heart Association (2022)
Background 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. Methods and Results 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. Conclusions The current study uncovers the pivotal role of endothelial fibulin-4 in the maintenance of valvulo-arterial integrity, which influences thoracic aortic aneurysm progression.
Keyphrases
- aortic valve
- endothelial cells
- high glucose
- aortic aneurysm
- single cell
- transcatheter aortic valve replacement
- transcatheter aortic valve implantation
- aortic stenosis
- aortic valve replacement
- spinal cord
- inflammatory response
- stem cells
- bone marrow
- high fat diet induced
- signaling pathway
- genome wide
- vascular endothelial growth factor
- induced apoptosis
- cell proliferation
- chronic obstructive pulmonary disease
- multiple sclerosis
- poor prognosis
- copy number
- heart failure
- preterm infants
- pulmonary artery
- epithelial mesenchymal transition
- pulmonary hypertension
- cell therapy
- intensive care unit
- dna methylation
- induced pluripotent stem cells
- coronary artery
- immune response
- type diabetes
- oxidative stress
- toll like receptor
- pi k akt
- south africa
- extracorporeal membrane oxygenation
- coronary artery disease
- drug induced
- skeletal muscle
- drug delivery
- data analysis