Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy

Abstract

Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3−/− mice, a model with congenital BAV formation. A combination of histological examination and in-vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3−/− mice. Moreover, cell lineage analysis and single cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3−/− mice. Spontaneous aortic dissections was found in ascending aortas located at the sinotubular junction in ∼13% of Nos3−/− mice. Moreover, Nos3−/−mice were prone to develop aortic dilations in the mid- and distal-ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3−/−mice as well as incomplete coverage of the aortic inner media by neural crest (NCC)-derived VSMCs. VSMCs of Nos3−/− showed downregulation of 15 genes of which 7 were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by Fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that disrupted endothelial mediated NO signalling in mice causes next to a congenital BAV also aortic dilation and dissection as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta of Nos3−/−mice.

Ventricular Septation and Outflow Tract Development in Crocodilians Result in Two Aortas With Bicuspid Semilunar Valves

“…In view of the human fragile aortic wall it is probably this third/noncoronary valve leaflet's etiology that associates with the differentiation of the outer media of the aortic wall, and that becomes prone to aneurysm formation. The inner media of the wall of the ascending aorta is NC derived [41,57], whereas the outer media/adventita is SHF derived [5,36]. We postulate that anomalous SHF differentiation may affect both this semilunar valve leaflet and the integrity of the ascending aorta.…”

Surgical Aortic Valve Replacement with Concomitant Aortic Surgery in Patients with Purely Bicuspid Aortic Valve and Associated Aortopathy

“…Adriana C. Gittenberger-de Groot and her team have performed an extensive number of indispensable studies on the spectrum of BAV disease and associated aortic anomalies over the past three decades. This contribution includes several developmental, histopathological, and anatomical studies on animal as well as human tissue, such as the meticulous explanation of cardiac development in congenital malformations [ 10 ], anatomical description of BAV and the aortic root [ 11 ], and the contribution of several cell lineages to the development of BAV and the associated aortic root anomalies [ 12 , 13 , 14 ]. In addition, other groups have reported that patient-specific factors such as aortic valve stenosis (AS), in combination with the specific leaflet morphology (the type of BAV) and the resultant shear stress, were associated with dilatation of the aorta [ 15 , 16 ].…”

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy

“…In this sense, Peterson et al used a mouse model deficient in NO synthase 3 ( Nos3 −/− ), essential for the balance of NO, which present congenital BAV. These mice developed dissections in the ascending aorta as a result of changes in NO signaling that disturb the profile of elastin [ 81 ]. Another study, carried out by Gauer et al, showed that in non-dilated ascending aorta wall from BAV patients, there were lower levels of NOS3 than in those with TAV.…”