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.
Faculty of Biological Sciences, Normandy University, UniRouen, PRIMACEN, Mont Saint Aignan, France.
Cardiovasc Res. 2023 Mar 31;119(2):492-505. doi: 10.1093/cvr/cvac086.
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.
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.
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.
淋巴管对心脏健康至关重要，而淋巴生成不足（淋巴管生成）会导致心肌梗死后心力衰竭（HF）的发展。然而，压力超负荷后非缺血性心肌病中淋巴管生成的调节和影响仍有待确定。在这里，我们研究了 C57Bl/6 和 Balb/c 小鼠以及终末期 HF 患者横主动脉缩窄（TAC）后的心脏淋巴管生成。
通过超声心动图评估心功能，通过免疫组织化学、流式细胞术、微量重力测量和基因表达分析评估心脏肥大、淋巴管、炎症、水肿和纤维化。应用中和抗 VEGFR3 抗体抑制小鼠心脏淋巴管生成。我们发现，VEGFR3 信号对于防止 C57Bl/6 小鼠 TAC 后心脏淋巴管稀疏是必不可少的。虽然抗 VEGFR3 诱导的淋巴管稀疏并没有显著加重 TAC 后心肌水肿，但心脏免疫细胞水平升高，特别是 3 周时的髓样细胞和 8 周时的 T 淋巴细胞。此外，尽管抑制淋巴管生成不会加重间质纤维化，但它会增加血管周围纤维化并加速左心室（LV）扩张和功能障碍的发展。在临床 HF 样本中，心脏淋巴管密度趋于增加，尽管淋巴管大小减小，特别是在扩张型心肌病患者中。同样，比较 C57Bl/6 和 Balb/c 小鼠后，TAC 后淋巴管重塑与 LV 扩张有关，而与肥大无关。Balb/c 小鼠中引人注目的淋巴管生成与 TAC 后 8 周时心脏中巨噬细胞、B 细胞和血管周围纤维化水平降低有关，而 C57Bl/6 小鼠的淋巴管生成较弱。然而，令人惊讶的是，这不足以解决心肌水肿，也不能预防 HF 的发展。
我们首次证明，内源性淋巴管生成限制 TAC 诱导的心脏炎症和血管周围纤维化，从而延缓 C57Bl/6 小鼠但不延缓 Balb/c 小鼠的 HF 发展。虽然 HF 患者中淋巴管重塑的功能影响仍有待确定，但我们的研究结果表明，在压力超负荷的情况下，心脏淋巴管生成不良可能会加速 HF 的发展。
