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

Date

2022

Authors

Martín Núñez, Ernesto
Garaikoetxea Zubillaga, Mattie
Navarro, Adela
Vico, Julieta Anabela
Arrieta Paniagua, Vanessa
García Peña, Amaia
Fernández Celis, Amaya
Gaínza Calleja, Alicia
Álvarez, Virginia

Director

Publisher

Frontiers Media
Acceso abierto / Sarbide irekia
Artículo / Artikulua
Versión publicada / Argitaratu den bertsioa

Project identifier

  • MINECO//CP13%2F00221/ES/ recolecta
  • ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F01875/ES/ recolecta
  • ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F00280/ES/ recolecta
  • ISCIII//FI19%2F00302/
  • ISCIII//CD19%2F00251/
Impacto

Abstract

Objective: We 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 Results: Totally 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-¿ 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. Conclusion: 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.

Description

Keywords

Angiogenesis, Aortic stenosis, Lymphangiogenesis, Sex, Valve interstitial cells

Department

Ciencias de la Salud / Osasun Zientziak

Faculty/School

Degree

Doctorate program

item.page.cita

Matilla, L., Martín-Núñez, E., Garaikoetxea, M., Navarro, A., Vico, J. A., Arrieta, V., García-Peña, A., Fernández-Celis, A., Gainza, A., Álvarez, V., Sádaba, R., López-Andrés, N., & Jover, E. (2022). Characterization of the sex-specific pattern of angiogenesis and lymphangiogenesis in aortic stenosis. Frontiers in Cardiovascular Medicine, 9. https://www.frontiersin.org/articles/10.3389/fcvm.2022.971802

item.page.rights

© 2022 Matilla, Martín-Núñez, Garaikoetxea, Navarro, Vico, Arrieta, García-Peña, Fernández-Celis, Gainza, Álvarez, Sádaba, López-Andrés and Jover. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)

Licencia

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