Klouda Timothy, Tsikis Savas T, Hirsch Thomas I, Kim Yunhye, Li Yan, Gaal Julia, Zhao Zhiyue, Friehs Ingeborg, Shyy John Y-J, Raby Benjamin A, Puder Mark, Yuan Ke
Division of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Biol Chem. 2025 May 8;301(6):110207. doi: 10.1016/j.jbc.2025.110207.
Patients with congenital heart disease causing significant left-to-right shunting of blood are at risk of developing pulmonary arterial hypertension (PAH). However, the underlying mechanism by which pulmonary overcirculation and shear stress drive vascular remodeling remains poorly understood. Our study established a "two-hit" murine model of severe pulmonary hypertension by combining left pneumonectomy (LP) and chronic hypoxia (LP/Hx). Using transgenic reporter lines, immunofluorescence staining, and advanced microscopy, we conducted cell-lineage tracing for vascular cells, including smooth muscle cells (SMCs), endothelial cells, and pericytes. Our findings reveal that SMCs are key contributors to the distal arteriolar remodeling following LP and LP/Hx. PCR analysis of SMCs isolated from LP/Hx animals demonstrated upregulation of markers associated with contractility, proliferation, and Cxcl12 expression. Consistently, CXCL12 was found to be overexpressed in the SMC layer of pulmonary vessels from patients with PAH-congenital heart disease. Lastly, in vitro experiments with healthy human pulmonary artery SMCs showed that laminar shear stress induces CXCL12 upregulation. These findings provide novel insights into the role of SMCs in flow-induced vascular remodeling and their mechanosensitive response to shear stress. This murine model of severe pulmonary hypertension is a valuable tool for future research and developing targeted therapeutics for patients with PAH.
患有导致大量血液从左向右分流的先天性心脏病患者有发生肺动脉高压（PAH）的风险。然而，肺循环过度和剪切应力驱动血管重塑的潜在机制仍知之甚少。我们的研究通过联合左肺切除术（LP）和慢性低氧（LP/Hx）建立了一种重度肺动脉高压的“两次打击”小鼠模型。利用转基因报告系、免疫荧光染色和先进显微镜技术，我们对包括平滑肌细胞（SMC）、内皮细胞和周细胞在内的血管细胞进行了细胞谱系追踪。我们的研究结果表明，SMC是LP和LP/Hx后远端小动脉重塑的关键促成因素。对从LP/Hx动物分离的SMC进行PCR分析显示，与收缩性、增殖和Cxcl12表达相关的标志物上调。同样，在先天性心脏病所致PAH患者的肺血管SMC层中发现CXCL12过表达。最后，对健康人肺动脉SMC进行的体外实验表明，层流剪切应力可诱导CXCL12上调。这些发现为SMC在血流诱导的血管重塑中的作用及其对剪切应力的机械敏感反应提供了新的见解。这种重度肺动脉高压小鼠模型是未来研究以及为PAH患者开发靶向治疗药物的宝贵工具。
