AUTHOR=Matilla Lara , Martín-Núñez Ernesto , Garaikoetxea Mattie , Navarro Adela , Vico Julieta Anabela , Arrieta Vanessa , García-Peña Amaia , Fernández-Celis Amaya , Gainza Alicia , Álvarez Virginia , Sádaba Rafael , López-Andrés Natalia , Jover Eva 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.971802

DOI=10.3389/fcvm.2022.971802

ISSN=2297-055X

ABSTRACT=Objective: We aim to analyse sex-related differences in angiogenesis and lymphangiogenesis in aortic valves (AVs) and valve interstitial cells (VICs) from aortic stenosis (AS) patients.
Approach and Results: 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’s. 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 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-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 VEGF-C, VEGF-D and VEGFR3 than women’s without changes in antiangiogenic markers.
Conclusions: Our 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.