Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure. Issue 2 (11th June 2022)

• Record Type: Journal Article
• Authors: Heron, Coraline; Dumesnil, Anais; Houssari, Mahmoud; Renet, Sylvanie; Lemarcis, Theo; Lebon, Alexis; Godefroy, David; Schapman, Damien; Henri, Orianne; Riou, Gaetan; Nicol, Lionel; Henry, Jean-Paul; Valet, Manon; Pieronne-Deperrois, Marie; Ouvrard-Pascaud, Antoine; Hagerling, Réné; Chiavelli, Hélène; Michel, Jean-Baptiste; Mulder, Paul; Fraineau, Sylvain; Richard, Vincent; Tardif, Virginie; Brakenhielm, Ebba
• Is Part Of: Cardiovascular research. Volume 119:Issue 2(2023)
• Page Start: 492
• Page End: 505
• Publication Date: 2022-06-11
• Subjects: Hypertrophy -- Vegfc -- Vegfd -- Inflammation -- Wall stress -- CCL21 -- mF4-31C1; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac086
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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. Graphical Abstract: Graphical Abstract Pressure-overload in mice leads to strain-dependent cardiac responses, with the development of either compensated or decompensated hypertrophy, accompanied by left ventricular (LV) dilation causing increased ventricular wall stress (WS). The compensated hypertrophic phenotype post-transversal aortic constriction (post-TAC), seen in female C57Bl/6 mice, was associated with transient and weak cardiac lymphangiogenesis, accumulation of immune cells and perivascular fibrosis. In contrast, both male C57Bl/6 and female Balb/c mice developed a dilated phenotype post-TAC, characterized by increased cardiac gene expression of ANP and IL1β, and stimulation of cardiac lymphangiogenesis. Inhibition of lymphangiogenesis during pressure-overload uncovered lymphatic rarefaction in the heart, with increased cardiac pro-inflammatory immune cell levels and aggravation of perivascular fibrosis, leading to accelerated development of cardiac remodelling and decompensation.