Deregulation of Notch1 pathway and circulating endothelial progenitor cell (EPC) number in patients with bicuspid aortic valve with and without ascending aorta aneurysm

Carmela R Balistreri,Calogera Pisano,Ernesto Greco,Elena Cavarretta,Sebastiano Sciarretta,Giacomo Frati,Leonardo Schirone,Giovanni Ruvolo,Maurizio Forte,Floriana Crapanzano,Antonino G M Marullo,Alberto Allegra

doi:10.1038/s41598-018-32170-2

Abstract

Bicuspid aortic valve (BAV) is frequently associated with the development of ascending aortic aneurysm, even if the underlying mechanisms remain to be clarified. Here, we investigated if a deregulation of Notch1 signaling pathway and endothelial progenitor cells (EPCs) number is associated with BAV disease and an early ascending aortic aneurysm (AAA) onset. For this purpose, 70 subjects with BAV (M/F 50/20; mean age: 58.8 ± 14.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M/F 35/35; mean age: 69.1 ± 12.8 years) and AAA complicated or not, were included. Interestingly, patients with AAA showed a significant increase in circulating Notch1 levels and EPC number than subjects without AAA. However, circulating Notch1 levels and EPC number were significantly lower in BAV subjects than TAV patients either in the presence or absence of AAA. Finally, Notch pathway was activated to a greater extent in aortic aneurysmatic portions with respect to healthy aortic fragments in both BAV and TAV patients. However, the expression of genes encoding components and ligands of Notch pathway in aortic tissues was significantly lower in BAV than TAV subjects. Our study demonstrates that BAV subjects are characterized by a significant decrease in both tissue and circulating levels of Notch pathway, and in blood EPC number than TAV patients, either in presence or absence of AAA disease.

Highlights

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, affecting approximately 1.3% of the population worldwide[1]
No significant differences were observed regarding the size of aorta dilatation between BAV and tricuspid aortic valve (TAV) cases affected by ascending aortic aneurysm (AAA)
Of 70 BAV cases, 51 subjects (73%; 45 males and 6 females; mean age: 50.6 ± 16.6 years) showed AAA with respect to only 25 TAV cases affected by AAA (36%; 19 males and 6 females; mean age: 70.2 ± 8.9 years) (p = 0.00001, by χ2 test, respectively)

Summary

Introduction

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, affecting approximately 1.3% of the population worldwide[1]. Aortic aneurysm development and rupture associated with BAV are likely the results of anomalous regulatory pathways in endothelial cells and vascular smooth muscle cells within the aortic media. These mechanisms remain to be fully clarified. Notch signaling pathway plays critical functions in the regulation of new vessel formation, neo-angiogenesis and vascular repair during stress[6,14,15,16]. A reduction of EPC number and function was previously found to be associated with the formation of cerebral and aortic aneurysm and inversely correlated with the size of aortic aneurysms[19,20]. The aim of our study was to investigate the interplay of Notch signaling pathway activity with EPC number, in BAV and AAA pathologies in a cohort of patients with BAV or TAV

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