Aortic valve stenosis burden: Where we are now?

Maffeis, Caterina; Rossi, Andrea; Faggiano, Pompilio

doi:10.1016/j.ijcard.2021.07.032

Cited by 3 publications

(3 citation statements)

References 9 publications

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“…The degeneration of AVs in AS involves structural damage such as inflammation, apoptosis, aberrant extracellular matrix remodelling (ECM), mineralization and neoangiogenesis, events associated with differentiation of VICs into myofibroblast or osteoblast-like cells [ 4 , 5 ]. Sex dimorphism exists in these AS pathological features [ 8 , 9 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence of the ageing population, its prevalence is rising promptly and is expected to double in the coming decade [ 1 – 3 ]. The pathogenesis of aortic valve (AV) stenosis is complex and includes features such as inflammation, fibrosis, angiogenesis and calcification [ 4 , 5 ]. Numerous studies support a sexual dimorphism in AS, both in clinical presentation and patient management, as well as in its pathobiology [ 6 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Sex-specific role of galectin-3 in aortic stenosis

Matilla,

Martín-Núñez,

Garaikoetxea

et al. 2023

Biol Sex Differ

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Background Aortic stenosis (AS) is characterized by inflammation, fibrosis, osteogenesis and angiogenesis. Men and women develop these mechanisms differently. Galectin-3 (Gal-3) is a pro-inflammatory and pro-osteogenic lectin in AS. In this work, we aim to analyse a potential sex-differential role of Gal-3 in AS. Methods 226 patients (61.50% men) with severe AS undergoing surgical aortic valve (AV) replacement were recruited. In AVs, Gal-3 expression and its relationship with inflammatory, osteogenic and angiogenic markers was assessed. Valve interstitial cells (VICs) were primary cultured to perform in vitro experiments. Results Proteomic analysis revealed that intracellular Gal-3 was over-expressed in VICs of male AS patients. Gal-3 secretion was also higher in men’s VICs as compared to women’s. In human AVs, Gal-3 protein levels were significantly higher in men, with stronger immunostaining in VICs with myofibroblastic phenotype and valve endothelial cells. Gal-3 levels in AVs were positively correlated with inflammatory markers in both sexes. Gal-3 expression was also positively correlated with osteogenic markers mainly in men AVs, and with angiogenic molecules only in this sex. In vitro, Gal-3 treatment induced expression of inflammatory, osteogenic and angiogenic markers in male’s VICs, while it only upregulated inflammatory and osteogenic molecules in women-derived cells. Gal-3 blockade with pharmacological inhibitors (modified citrus pectin and G3P-01) prevented the upregulation of inflammatory, osteogenic and angiogenic molecules. Conclusions Gal-3 plays a sex-differential role in the setting of AS, and it could be a new sex-specific therapeutic target controlling pathological features of AS in VICs. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex-specific role of galectin-3 in aortic stenosis

Matilla,

Martín-Núñez,

Garaikoetxea

et al. 2023

Biol Sex Differ

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“…Aortic stenosis (AS) is a major health problem that affects 2 to 7% of individuals older than 65 years ( 1 ). There are currently no pharmacological strategies to prevent, delay, or reverse AS ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the sex-specific pattern of angiogenesis and lymphangiogenesis in aortic stenosis

Matilla

Martín‐Núñez

Garaikoetxea

et al. 2022

Front. Cardiovasc. Med.

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ObjectiveWe aim to analyze sex-related differences in angiogenesis and lymphangiogenesis in aortic valves (AVs) and valve interstitial cells (VICs) from aortic stenosis (AS) patients.Approach and ResultsTotally 230 patients (59% men) with severe AS undergoing surgical valve replacement were recruited. The density of total neovessels was higher in AVs from men as compared to women. Both small and medium neovessels were more abundant in men's AVs. Accordingly, male AVs exhibited higher CD31 and VE-cadherin expressions. The levels of the pro-angiogenic markers, such as vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, insulin-like growth factor-binding protein-2 (IGFBP-2), interleukin (IL)-8, chemerin, and fibroblast growth factor (FGF)-7, were increased in AVs from men. Transforming growth factor-β expression was higher in male AVs. The expression of antiangiogenic molecules thrombospondin (Tsp)-1, endostatin, and CD36 was upregulated in male AVs, although the levels of Tsp-2, IL-4, IL-12p70, and chondromodulin-1 were similar between both sexes. The number of lymphatic vessels and the expression of the lymphangiogenic markers Lyve-1 and D2-40 was higher in men's AV as well as VEGF-C, VEGF-D, and VEGFR3. Multivariate analyses adjusted for confounders further validated the sex-dependent expression of these targets. VICs isolated from men's AVs secreted higher amounts of the pro-angiogenic factors, VEGF-A, VEGFR1, IGFBP-2, and FGF-7, as well as the pro-lymphangiogenic factors, VEGF-C, VEGF-D, and VEGFR3, than women without changes in antiangiogenic markers.ConclusionOur data show that aberrant angiogenic and lymphangiogenic cues are over-represented in male AVs. Importantly, the VIC is a relevant source of multiple morphogens involved in angiogenesis and lymphangiogenesis likely endowing the AV of men with the predominant calcific AS phenotypes.

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