From the Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, National Clinical Research Center for Hematologic Diseases, State Key Laboratory of Radiation Medicine and Protection, Cam-Su Genomic Resources Center, Soochow University, Suzhou, China (H.J., L.Z., X. Liu, C.C., X. Li, T.L., Z.S., Y.H.).
MOE Key Laboratory for Model Animal and Disease Study, Model Animal Research Institute, Nanjing University, China (L.Z., W.S., W.H., F.Z., Q.X., Z.Y., X.G.).
Arterioscler Thromb Vasc Biol. 2020 Apr;40(4):958-972. doi: 10.1161/ATVBAHA.119.313901. Epub 2020 Feb 13.
Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells () led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with knockout in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of mutants. The SMAD3 (mothers against decapentaplegic homolog 3) phosphorylation (pSMAD3) was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells of mice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels in mutant mice.
The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.
血管壁构建和维持过程中，内皮-壁细胞相互作用的脉管生成因子的特征尚不完全清楚。本研究旨在探讨内皮细胞衍生的 FSTL1（卵泡抑素样蛋白 1）在血管稳态中的作用。
利用条件性基因敲除小鼠模型，我们发现内皮细胞中 FSTL1 的缺失导致肺血管阻力增加，从而导致心脏反流，尤其是三尖瓣反流。然而，在平滑肌细胞或造血细胞中缺失的突变小鼠中并未检测到这种异常。我们进一步表明，内皮细胞 FSTL1 缺失后，心房心内膜、心脏瓣膜、静脉和微血管中存在过多的αSMA（α-平滑肌肌动蛋白）。在 突变体的肝脏中也观察到胶原沉积增加。SMAD3（mothers against decapentaplegic homolog 3）磷酸化（pSMAD3）显著增强，pSMAD3 染色与静脉壁中的 αSMA 共定位，提示 TGFβ（转化生长因子 β）信号在 小鼠的血管壁细胞中被激活。一致地，TGFβ 通路抑制剂的治疗降低了 突变小鼠中 αSMA 与心房和血管的异常关联。
这些发现表明，内皮 FSTL1 对血管壁的稳态至关重要，其不足可能有利于心血管纤维化导致心力衰竭。
