Variants in the gene encoding endothelial nitric oxide synthase (eNOS) have been associated with cardiovascular diseases in adults, and mice lacking eNOS develop a broad range of cardiovascular phenotypes. However, the aetiology of these pathologies is not fully understood.

Henderson and colleagues explored cardiovascular abnormalities in eNOS-null foetuses, neonates and adults to ascertain the role of eNOS in both congenital and adult-onset cardiovascular pathologies in mice. First, the authors outlined that mortality was significantly higher in eNOS-null foetuses and neonates than in control mice. This increased mortality was attributed to abnormalities in the ventricular myocardium and, in neonates, pulmonary abnormalities. The authors then examined surviving adult eNOS-null mice and found evidence of cardiac hypertrophy, aortopathy and cartilaginous metaplasia, which is aberrant cartilage formation. Cartilaginous metaplasia was observed in the aortic arch, where the authors also identified loss of smooth muscle cells and neural crest cells (NCCs).

Even though cartilaginous metaplasia only presented in adult eNOS-null mice, abnormalities in the thoracic aorta and its associated aortic arch arteries were apparent in the same region in late gestation, including loss of NCCs and aberrant expression of markers of chondrocytes that are responsible for cartilage formation. In eNOS-null foetuses, NCC loss led to a reduction in baroreceptors, which are important for homeostatic responses to changes in blood pressure. Consequently, eNOS-null adult mice were more hypertensive under normal and induced conditions compared to control mice.

Interestingly, the authors found that disrupted Notch signalling in eNOS-null foetuses preceded the altered pro-chondrogenic signalling in the aortic arch. Notch signalling is also known to be important for the differentiation and maturation of smooth muscle cell lineages, and this aberrant signalling was detected during a developmental stage critical for the differentiation of smooth muscle cells that form the aortic arch in adulthood.

By tracking cardiac abnormalities from development to adulthood, the authors concluded that eNOS is important for heart and aorta development, most likely via its regulation of Notch signalling. These findings suggest that eNOS could be a key factor in congenital conditions and that some adult-onset cardiovascular diseases, such as hypertension, may have congenital origins.

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Eley
,
L.
,
Richardson
,
R. V.
,
Alqahtani
,
A.
,
Chaudhry
,
B.
and
Henderson
,
D. J.
(
2024
).
eNOS plays essential roles in the developing heart and aorta linked to disruption of Notch signalling
.
Dis. Model. Mech.
17
,
dmm050265
. doi:10.1242/dmm.050265
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