Spurgin Stephen, Thai Lauren, Wan Tina, Chaney Christopher P, Cowdin Mitzy A, Reddy Suren V, Tarique Hussain M, Fares Munes, Carroll Thomas, Spearman Andrew D, Cleaver Ondine
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas, USA 75390.
Department of Pediatrics, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas, USA 75390.
bioRxiv. 2025 Jul 2:2025.06.30.662470. doi: 10.1101/2025.06.30.662470.
Single ventricle congenital heart disease (SV-CHD) is a uniformly lethal condition. Survival depends upon the Glenn surgery, which shunts venous blood directly to the pulmonary arteries without the support of a pumping ventricle. In the context of this altered circulation (loss of cardiac-driven pulsatility), diverse pulmonary vascular complications develop, severely limiting survival. To date, the relationship between loss of arterial pulsatility and pulmonary vascular changes has not yet been investigated at the cellular level.
Using combined cardiac catheterization and cardiac MRI, we defined pulsatility loss in three dimensions (flow, pressure, and stretch) in the pulmonary arteries of SV-CHD patients in the Glenn stage. To assess the impact of pulsatility loss on endothelial cells (ECs), we exposed cultured human pulmonary artery endothelial cells to individual dimensions of force. We used bulk RNA sequencing, GSEA, ELISA, and immunofluorescent staining to investigate cellular changes. A rat model of the Glenn circulation was used to further assess the cellular adaptation of pulmonary arteries to non-pulsatile hemodynamic forces.
We identify and quantify pulsatility loss in Glenn patients, occurring in all three dimensions of hemodynamic force. We show unique transcriptional signatures of pulsatility within each dimension of force, affecting key structural and signaling pathways in ECs. We identify pulsatile stretch as a critical stimulus for endothelial secretion of PDGFB-a known driver of vascular smooth muscle cell (vSMC) proliferation and vascular wall recruitment. Moreover, we show that loss of arterial pulsatility leads to thinning of the vascular wall and reduction of VSMCs.
This work identifies a novel and critical role for blood flow pulsatility in maintenance of the pulmonary vascular architecture. Our study provides a mechanistic understanding of the role of pulsatile, arterial forces in maintaining normal pulmonary vascular architecture through EC-SMC crosstalk. Arterial pulsatility is sensed by stretch of endothelial cells and relayed via PDGFB to the vascular smooth muscle, thus maintaining a vascular structure that can support arterial hemodynamic force.
单心室先天性心脏病（SV-CHD）是一种必死无疑的疾病。其存活依赖于格林手术，该手术可将静脉血直接分流至肺动脉，而无需泵血心室的支持。在这种改变的循环（心脏驱动的搏动性丧失）背景下，会出现多种肺血管并发症，严重限制了存活率。迄今为止，尚未在细胞水平研究动脉搏动性丧失与肺血管变化之间的关系。
我们通过联合心脏导管插入术和心脏磁共振成像，在格林阶段的SV-CHD患者肺动脉中从三个维度（流量、压力和拉伸）定义搏动性丧失。为了评估搏动性丧失对内皮细胞（ECs）的影响，我们将培养的人肺动脉内皮细胞暴露于各个力的维度。我们使用批量RNA测序、基因集富集分析（GSEA）、酶联免疫吸附测定（ELISA）和免疫荧光染色来研究细胞变化。使用格林循环大鼠模型进一步评估肺动脉对非搏动性血流动力学力的细胞适应性。
我们识别并量化了格林患者的搏动性丧失，其发生在血流动力学力的所有三个维度中。我们展示了每个力维度内搏动性的独特转录特征，影响内皮细胞中的关键结构和信号通路。我们确定搏动性拉伸是内皮细胞分泌血小板衍生生长因子B（PDGFB）的关键刺激因素，PDGFB是血管平滑肌细胞（vSMC）增殖和血管壁募集的已知驱动因素。此外我们表明，动脉搏动性丧失会导致血管壁变薄和血管平滑肌细胞减少。
这项研究确定了血流搏动性在维持肺血管结构方面的新的关键作用。我们的研究提供了一种机制性理解，即搏动性动脉力通过内皮细胞-平滑肌细胞相互作用在维持正常肺血管结构中的作用。动脉搏动性通过内皮细胞的拉伸被感知，并通过PDGFB传递给血管平滑肌，从而维持能够支持动脉血流动力学力的血管结构。
