Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions

Abstract

Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm.

Unraveling the Molecular Complexity of Bicuspid Aortopathy: Lessons from Comparative Proteomics

“…During the last decade, several key molecular pathways have been found to contribute to aneurysm formation, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII, supported by numerous independent evidence [23][24][25][26][27] . However, although both experimental and human studies support the involvement of these pathways, it is recognized that the evidence base remains fragmentary.…”

“…Remarkably, we found dysregulation of four of these pathways in TBAV animals, attributed to the altered expression of nine proteins in those pathways (Fig.4). LTBP3, TGF-β, EGFR, SMAD2, REHB and MAPK1/2, involved in downregulation of contractile proteins 24 were found upregulated, whereas GSK3b and β-catenin, involved in the differentiation of SMCs to the contractile phenotype 45 were downregulated. These alterations are concordant with SMC shifting towards the synthetic phenotype, which was supported by the reduced number of α-Actin + aortic SMCs in TBAV animals (Fig.3A-D).…”

“…In our dataset, this pathway exhibits the most significant alterations, with five upregulated (SMAD2, IKK, RHEB, MAP2K1/2, and eNOS) and four downregulated (LTBP3, SMAP2, PP2A, and CTNNB1) proteins in TBAV hamsters (Fig.4). Notably, most of these proteins are independently altered in different patient populations 8,23,24,26,28,29 . In SMCs of some BAV patients, the overactivation of PI3K/AKT pathway results from an increase of pAKT, regardless of the aortic diameter, suggesting a congenital predisposition of these patients 30 .…”

“…However, although both experimental and human studies support the involvement of these pathways, it is recognized that the evidence base remains fragmentary. The key missing question, as experts have already pointed out 24 , is whether these pathways are functionally interconnected in the ascending aorta, such that the combination of their alterations causes cellular dysfunction, ultimately leading to tissue deterioration. Alternatively, different molecular pathway alterations may characterize an etiologically distinct patient population.…”

The key role of miRNA in syndromic and sporadic forms of ascending aortic aneurysms as biomarkers and targets of novel therapeutic strategies

“…The regulation of gene expression appears to be quite interesting, especially considering the complex pathophysiological mechanisms underlying the sporadic forms of aortic aneurysms ( Balistreri, 2015 ; Pisano et al, 2017 ; Saeyeldin et al, 2019 ), which are the result of a close interaction between genetic and modifiable lifestyle factors (e.g., diet, smoking, infections, drug use, alcohol, sedentary lifestyle, etc.) ( Zhou et al, 2018 ; Downey and Aron, 2022 ; Zhou et al, 2022 ; Bararu et al, 2023 ; Chung, 2023 ; Crousillat et al, 2023 ; Dong et al, 2023 ; Salmasi et al, 2023 ) ( Figure 1 ). However, male gender, age over 65 years, and a history of smoking are considered the main risk factors, although genetic factors are important in their development ( Balistreri, 2015 ; Pisano et al, 2017 ; Hayder et al, 2018 ; Saeyeldin et al, 2019 ).…”