Studies on sporadic non-syndromic thoracic aortic aneurysms: 1. Deregulation of Jagged/Notch 1 homeostasis and selection of synthetic/secretor phenotype smooth muscle cells

Abstract

Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. The study aimed at defining the peculiar morphologic and molecular changes occurring in the media layer of SNSTAAs. Design This study was based on a single centre design. Methods Media layer samples taken from seven carefully selected SNSTAAs and seven reference patients (controls) were investigated via quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, quantitative histology, and immunohistochemistry/immunofluorescence. Results In SNSTAAs media, aortic smooth muscle cells numbers were halved due to an apoptotic process coupled with a negligible cell proliferation. Cystathionine γ-lyase was diffusely up-regulated. Surviving aortic smooth muscle cells exhibited diverging phenotypes: in inner- and outer-media contractile cells prevailed, having higher contents of smooth-muscle-α-actin holoprotein (45-kDa) and of caspase-3-cleaved smooth-muscle-α-actin 25-kDa fragments; in mid-media, aortic smooth muscle cells exhibited a synthetic/secretor phenotype, down-regulating vimentin, but up-regulating glial fibrillary acidic protein, trans-Golgi network 46 protein, Jagged1 (172-kDa) holoprotein, and Jagged1's receptor Notch1. Extracellular soluble Jagged1 (42-kDa) fragments accumulated. Conclusions In SNSTAAs, there is a relentless aortic smooth muscle cells attrition caused by the up-regulated cystathionine γ-lyase. In mid-media, synthetic/secretor aortic smooth muscle cells intensify Jagged1/NOTCH1 signalling in the attempt to counterbalance the weakened aortic wall, due to aortic smooth muscle cells net loss and mechanical stress. Synthetic/secretor aortic smooth muscle cells are apoptosis-prone, and the accruing thrombin-cleaved Jagged1 fragments counteract the otherwise useful effects of Jagged1/NOTCH1 signalling, thus hampering tissue homeostasis/remodelling, and aortic smooth muscle cells adhesion, differentiation, and migration.

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

“…However, Notch signaling antagonizes TGF-β signaling by reducing the expression of TGF-β receptor II via the induction of miR145 [180]; in turn, TGF-β antagonizes Notch signaling by decreasing the expression of Notch3 [181]. The expression of Notch ligands and receptors is dysregulated in TAA, and defective Notch signaling has been associated with TAA that develops in patients with malformations of the aortic valve [175,182,183].…”

“…In mouse models, Notch1 haploinsufficiency causes aortic dilation in mice of a permissive genetic background (129S6) and exacerbates aortic root pathology of MFS mouse models, independently of aortic valve defects [329]. Although the mechanisms by which loss of Notch signaling causes TAA remain unclear, defective developmental interactions between endothelial cells and VSMCs, and direct effects on VSMC phenotype have both been proposed [175,183,330]. Notably, whereas Notch signaling appears to be protective in TAA, it tends to exacerbate inflammation-driven AAA [175,331,332].…”

Studies on sporadic non-syndromic thoracic aortic aneurysms: II. Alterations of extra-cellular matrix components and focal adhesion proteins

“…We reported that in SNSTAAs an increased JAG1NOTCH1 signalling was interfered by the proteolysis of JAG1 and the formation of a dominant-negative soluble JAG1 fragment. 28 The reduced availability of MAGP1 protein we observed would further lessen JAG1NOTCH1 signalling and its positive consequences on tissue remodelling in the media layer of SNSTAAs. Previous studies showed that the MAGP1-deficient mouse suffers from two healing defects: a delayed clot formation in response to endothelial damage, and a delayed healing of incisional skin wounds.…”

Notch signalling in healthy and diseased vasculature

“…The VSMC-specific elimination of Jagged1 [ 116 ] or the combined loss of Notch3 and specific ablation of Notch2 in VSMCs [ 117 ] results in a PDA-like phenotype in mice. Furthermore, NOTCH1 gene variants were observed in patients with aortic coarctation and aortic aneurysm (for a review see [ 118 ]), and aberrant expression of Notch pathway genes was noted in patients with thoracic aortic aneurysm [ 119 , 120 ].…”