Nicolas Gendron1,2, Mickael Rosa3, Adeline Blandinieres1,2, Yoann Sottejeau3, Elisa Rossi1,2, Eric Van Belle3, Salim Idelcadi1,4, Séverine Lecourt1,2, André Vincentelli3, Audrey Cras1,5, Ramadan Jashari6, Richard Chocron7,8, Yaël Baudouin9, Thibault Pamart3, Ivan Bièche10, Nathalie Nevo1,2, Bernard Cholley4, Jeanne Rancic1,2, Bart Staels3, Pascale Gaussem1,2, Annabelle Dupont3, Alain Carpentier11, Sophie Susen3, David M Smadja1,2. 1. Université de Paris, Innovative Therapies in Haemostasis, INSERM, France (N.G., A.B., E.R., S.I., S.L., A. Cras, N.N., J.R., P.G., D.M.S.). 2. Hematology Department and Biosurgical Research Lab (Carpentier Foundation) (N.G., A.B., E.R., S.L., N.N., J.R., P.G., D.M.S.), AH-HP, Georges Pompidou European Hospital, France. 3. University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, France (M.R., Y.S., E.V.B., A.V., T.P., B.S., A.D., S.S.). 4. Department of Anesthesia and Intensive Care and Biosurgical Research Lab (Carpentier Foundation) (S.I., B.C.), AH-HP, Georges Pompidou European Hospital, France. 5. Cell therapy Department, AH-HP, Saint Louis Hospital, Paris, France (A. Cras). 6. European Homograft Bank, Clinic Saint Jean, Brussels, Belgium (R.J.). 7. Emergency Medicine Department (R.C.), AH-HP, Georges Pompidou European Hospital, France. 8. Université de Paris, PARCC, INSERM, France (R.C.). 9. Hematology Department, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France (Y.B.). 10. Department of Genetics, Pharmacogenomics Unit, Institut Curie, Paris, France (I.B.). 11. Université de Paris, Biosurgical Research Lab (Carpentier Foundation) (A. Carpentier), AH-HP, Georges Pompidou European Hospital, France.
Abstract
OBJECTIVE: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VICp) mesenchymal-like phenotype was confirmed by CD90+/CD73+/CD44+ expression and multipotent-like differentiation ability. When VICp were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VICp and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VICp-conditioned media and confirmed at the mRNA level in VICp compared with control VIC. Conditioned media from VICp induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VICp involvement in angiogenesis by a VEGF-A dependent mechanism. CONCLUSIONS: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VICp in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.
OBJECTIVE: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VICp) mesenchymal-like phenotype was confirmed by CD90+/CD73+/CD44+ expression and multipotent-like differentiation ability. When VICp were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VICp and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VICp-conditioned media and confirmed at the mRNA level in VICp compared with control VIC. Conditioned media from VICp induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VICp involvement in angiogenesis by a VEGF-A dependent mechanism. CONCLUSIONS: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VICp in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.
Authors: Rolando A Cuevas; Claire C Chu; William J Moorhead; Ryan Wong; Ibrahim Sultan; Cynthia St Hilaire Journal: J Vis Exp Date: 2021-04-16 Impact factor: 1.355
Authors: Thomas Senage; Anu Paul; Thierry Le Tourneau; Imen Fellah-Hebia; Marta Vadori; Salam Bashir; Manuel Galiñanes; Tomaso Bottio; Gino Gerosa; Arturo Evangelista; Luigi P Badano; Alberto Nassi; Cristina Costa; Galli Cesare; Rizwan A Manji; Caroline Cueff de Monchy; Nicolas Piriou; Romain Capoulade; Jean-Michel Serfaty; Guillaume Guimbretière; Etienne Dantan; Alejandro Ruiz-Majoral; Guénola Coste du Fou; Shani Leviatan Ben-Arye; Liana Govani; Sharon Yehuda; Shirley Bachar Abramovitch; Ron Amon; Eliran Moshe Reuven; Yafit Atiya-Nasagi; Hai Yu; Laura Iop; Kelly Casós; Sebastián G Kuguel; Arnau Blasco-Lucas; Eduard Permanyer; Fabrizio Sbraga; Roger Llatjós; Gabriel Moreno-Gonzalez; Melchor Sánchez-Martínez; Michael E Breimer; Jan Holgersson; Susann Teneberg; Marta Pascual-Gilabert; Alfons Nonell-Canals; Yasuhiro Takeuchi; Xi Chen; Rafael Mañez; Jean-Christian Roussel; Jean-Paul Soulillou; Emanuele Cozzi; Vered Padler-Karavani Journal: Nat Med Date: 2022-02-17 Impact factor: 87.241
Authors: Robert B Hinton; Amy L Juraszek; Amy M Opoka; Benjamin J Landis; J Michael Smith; Robert P Mecham; Kevin E Bove Journal: J Cardiovasc Dev Dis Date: 2021-06-25