Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells
Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells
复制标题
DOI：
10.1242/jcs.239715
复制
发表时间：
2020-07-01
影响因子：
4
通讯作者：
Morrell, Nicholas W.
中科院分区：
文献类型：
--
作者：
Upton, Paul D.;Park, John E. S.;Morrell, Nicholas W.
骨形态发生蛋白9(BMP9)和骨形态发生蛋白10(BMP10)是通过I型受体ALK1和II型受体激活素IIA受体(ACTR-IIA)和骨形态发生II型受体(BMPR-II)的复合体介导内皮细胞保护的循环配体。我们已证实BMP9可诱导内皮细胞表达IL-6、IL-8和E-选择素，并可能影响其与单核细胞和中性粒细胞的相互作用。我们询问BMP9和BMP10是否调节趋化因子(C-C基序)配体2(CCL2)的表达，CCL2是参与单核巨噬细胞化学吸引的关键趋化因子。在这里，我们发现BMP9和BMP10抑制人肺动脉内皮细胞和主动脉内皮细胞基础CCL2的表达和释放。这种抑制依赖于ALK1，并共同依赖于ACTR-IIA和BMPR-II。对典型Smad信号的评估表明，这种反应依赖于Smad4。值得注意的是，Smad1/5信号只有在BMP9浓度与循环中的浓度相似时才起作用。在炎症的背景下，BMP9不改变由肿瘤坏死因子-α诱导的CCU。由于CCL2促进单核/巨噬细胞趋化和内皮通透性，这些数据支持BMP9保护基础内皮完整性的概念。
Bone morphogenetic protein 9 (BMP9) and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor ALK1 and the type II receptors activin type-IIA receptor (ACTR-IIA) and bone morphogenetic type II receptor (BMPR-II). We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and might influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte-macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. The repression was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCU by TNF-alpha. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.