Gynecology Research Unit, Hannover Medical School, Hannover, Germany.
Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
FASEB J. 2022 Jul;36(7):e22379. doi: 10.1096/fj.202200040RR.
Preeclampsia, a pregnancy-related hypertensive disorder, is associated with endothelial dysfunction and increased cardiovascular risk of the offspring in adulthood. In preeclampsia, endothelial colony-forming cells (ECFC) are reduced in number and function. Recently, we have shown that miR-1270, which is involved in cancer in vitro proliferation, migration, and tumor progression, is downregulated in fetal ECFC from preeclamptic pregnancies. We now hypothesize that miR-1270 dysregulation contributes to vascular endothelial dysfunction occurring after preeclampsia via ATM (ataxia telangiectasia mutated) overexpression, the key kinase of DNA damage repair. Here, we show that miR-1270 silencing in normal ECFC and downregulation in preeclamptic ECFC are accompanied by an increase in the expression levels of ATM. Furthermore, ATM activation correlates with upregulated tyrosine kinase Src leading to phosphorylation and internalization of VE-cadherin (vascular endothelial-cadherin) which subsequently compromises endothelial barrier permeability and morphodynamic cell parameters. Treatment with specific ATM inhibitors reveals a novel role of ATM upstream of tyrosine kinase Src activation. Subsequently, Src phosphorylation and internalization of VE-cadherin compromise endothelial barrier permeability. Our findings suggest that downregulation of miR-1270 contributes to impaired ECFC function via the associated ATM overexpression, which further identifies ATM as a novel and critical factor for ECFC defects in preeclampsia. Our study provides new insights into the understanding of ECFC impairment associated with cardiovascular risk in preeclamptic offspring and identifies potential novel therapeutic targets.
子痫前期是一种与妊娠相关的高血压疾病，与内皮功能障碍和成年后代心血管风险增加有关。在子痫前期中，内皮祖细胞（endothelial colony-forming cells，ECFC）的数量和功能减少。最近，我们发现 miR-1270 在体外参与癌症的增殖、迁移和肿瘤进展，在子痫前期胎儿 ECFC 中下调。我们现在假设 miR-1270 失调通过 ATM（ataxia telangiectasia mutated）过表达导致血管内皮功能障碍，而 ATM 是 DNA 损伤修复的关键激酶。在这里，我们表明 miR-1270 在正常 ECFC 中的沉默和在子痫前期 ECFC 中的下调伴随着 ATM 表达水平的增加。此外，ATM 的激活与上调的酪氨酸激酶Src 相关，导致血管内皮钙黏蛋白（vascular endothelial-cadherin，VE-cadherin）的磷酸化和内化，随后损害内皮屏障通透性和形态动力学细胞参数。特异性 ATM 抑制剂的治疗揭示了 ATM 在 Src 激活上游的新作用。随后，Src 的磷酸化和 VE-cadherin 的内化损害内皮屏障通透性。我们的研究结果表明，miR-1270 的下调通过相关的 ATM 过表达导致 ECFC 功能受损，这进一步确定 ATM 是子痫前期 ECFC 缺陷的一个新的关键因素。我们的研究为理解与子痫前期后代心血管风险相关的 ECFC 损伤提供了新的见解，并确定了潜在的新的治疗靶点。
