Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure.

Autor:	Heron C; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Dumesnil A; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Houssari M; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Renet S; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Lemarcis T; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Lebon A; Faculty of Biological Sciences, Normandy University, UniRouen, PRIMACEN, Mont Saint Aignan, France., Godefroy D; Faculty of Biological Sciences, Normandy University, UniRouen, Inserm UMR1239 (DC2N Laboratory), Mont Saint Aignan, France., Schapman D; Faculty of Biological Sciences, Normandy University, UniRouen, PRIMACEN, Mont Saint Aignan, France., Henri O; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Riou G; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1234 (PANTHER Laboratory), Rouen, France., Nicol L; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Henry JP; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Valet M; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Pieronne-Deperrois M; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Ouvrard-Pascaud A; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Hagerling R; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical and Human Genetics, Augustenburger Platz 1, 13353 Berlin, Germany.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany., Chiavelli H; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Michel JB; UMR 1148, Inserm-Paris University, X. Bichat Hospital, Paris, France., Mulder P; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Fraineau S; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Richard V; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Tardif V; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France., Brakenhielm E; Faculty of Pharmacy and Medicine, Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU CARNAVAL, Rouen, France.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 Mar 31; Vol. 119 (2), pp. 492-505.
DOI:	10.1093/cvr/cvac086
Abstrakt:	Aims: Lymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphangiogenesis in non-ischaemic cardiomyopathy following pressure-overload remains to be determined. Here, we investigated cardiac lymphangiogenesis following transversal aortic constriction (TAC) in C57Bl/6 and Balb/c mice, and in end-stage HF patients. Methods and Results: Cardiac function was evaluated by echocardiography, and cardiac hypertrophy, lymphatics, inflammation, oedema, and fibrosis by immunohistochemistry, flow cytometry, microgravimetry, and gene expression analysis. Treatment with neutralizing anti-VEGFR3 antibodies was applied to inhibit cardiac lymphangiogenesis in mice. We found that VEGFR3-signalling was essential to prevent cardiac lymphatic rarefaction after TAC in C57Bl/6 mice. While anti-VEGFR3-induced lymphatic rarefaction did not significantly aggravate myocardial oedema post-TAC, cardiac immune cell levels were increased, notably myeloid cells at 3 weeks and T lymphocytes at 8 weeks. Moreover, whereas inhibition of lymphangiogenesis did not aggravate interstitial fibrosis, it increased perivascular fibrosis and accelerated development of left ventricular (LV) dilation and dysfunction. In clinical HF samples, cardiac lymphatic density tended to increase, although lymphatic sizes decreased, notably in patients with dilated cardiomyopathy. Similarly, comparing C57Bl/6 and Balb/c mice, lymphatic remodelling post-TAC was linked to LV dilation rather than to hypertrophy. The striking lymphangiogenesis in Balb/c was associated with reduced cardiac levels of macrophages, B cells, and perivascular fibrosis at 8 weeks post-TAC, as compared with C57Bl/6 mice that displayed weak lymphangiogenesis. Surprisingly, however, it did not suffice to resolve myocardial oedema, nor prevent HF development. Conclusions: We demonstrate for the first time that endogenous lymphangiogenesis limits TAC-induced cardiac inflammation and perivascular fibrosis, delaying HF development in C57Bl/6 but not in Balb/c mice. While the functional impact of lymphatic remodelling remains to be determined in HF patients, our findings suggest that under settings of pressure-overload poor cardiac lymphangiogenesis may accelerate HF development. Competing Interests: Conflict of interest: The authors declare that no conflict of interest exists. (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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