Allerkamp Hanna H, Bondarenko Alexander I, Tawfik Ines, Kamali-Simsek Nilüfer, Horvat Mercnik Monika, Madreiter-Sokolowski Corina T, Wadsack Christian
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
BioTechMed-Graz, Graz, Austria.
Am J Physiol Cell Physiol. 2025 Jan 1;328(1):C227-C244. doi: 10.1152/ajpcell.00794.2024. Epub 2024 Dec 9.
Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE), impacting offspring health. The ion channels Piezo-type mechanosensitive ion channel component 1 (Piezo1) and transient receptor potential cation channel subfamily V member 4 (TRPV4) are coregulated mechanosensors in ECs. Current evidence suggests that both channels could mediate aberrant placental endothelial function in EPE. Using isolated fetoplacental ECs (fpECs) from early control (EC) and EPE pregnancies, we show functional coexpression of both channels and that Ca influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs and has a stronger effect on EPE fpECs. This implies altered Piezo1-TRPV4 coregulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA sequencing. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future. This study shows Piezo-type mechanosensitive ion channel component 1 (Piezo1) and transient receptor potential cation channel subfamily V member 4 (TRPV4) coexpression and functionality within primary human fetoplacental endothelial cells (fpECs), mediating nitric oxide (NO) production and barrier integrity. In early-onset preeclampsia (EPE), fpEC channel functionality and coregulation are impaired, affecting Ca signaling and endothelial barrier function. Combined channel activation significantly reduces endothelial barrier integrity and increases NO production in EPE. Changes in arachidonic acid metabolism are suggested as a key underlying factor mediating impaired channel functionality in EPE fpECs.
机械感觉对于内皮细胞（EC）功能至关重要，而在早发型子痫前期（EPE）中内皮细胞功能受损，会影响后代健康。离子通道压电型机械敏感离子通道组分1（Piezo1）和瞬时受体电位阳离子通道亚家族V成员4（TRPV4）是内皮细胞中的共同调节机械传感器。目前的证据表明，这两种通道都可能介导EPE中胎盘内皮功能异常。使用来自早期对照（EC）和EPE妊娠的分离的胎儿胎盘内皮细胞（fpEC），我们显示了这两种通道的功能性共表达，并且在EPE fpEC中，响应化学通道激活的钙内流和膜去极化减少。在通道激活的下游，仅Piezo1就能诱导fpEC中内皮型一氧化氮合酶（eNOS）的磷酸化，而Piezo1和TRPV4的联合激活仅影响EPE fpEC中eNOS的磷酸化。此外，联合激活会降低fpEC的屏障完整性，并且对EPE fpEC有更强的影响。这意味着EPE中Piezo1-TRPV4的共同调节发生了改变。从机制上讲，我们认为这是由EPE fpEC中花生四烯酸代谢的变化驱动的，这是通过RNA测序确定的。靶向Piezo1和TRPV4可能在未来为EPE治疗提供选择。这项研究显示了压电型机械敏感离子通道组分1（Piezo1）和瞬时受体电位阳离子通道亚家族V成员4（TRPV4）在原代人胎儿胎盘内皮细胞（fpEC）中的共表达和功能，介导一氧化氮（NO）的产生和屏障完整性。在早发型子痫前期（EPE）中，fpEC通道功能和共同调节受损，影响钙信号传导和内皮屏障功能。联合通道激活显著降低内皮屏障完整性并增加EPE中的NO产生。花生四烯酸代谢的变化被认为是介导EPE fpEC中通道功能受损的关键潜在因素。
