Murine Aortopulmonary Shunt Model of Flow-Driven Pulmonary Hypertension-Brief Report

Chronic left-to-right shunting, as occurs with congenital heart disease or persistent ductus-like flow, exposes pulmonary circulation to sustained high-flow shear and pulsatile pressure and causes severe, flow-mediated arteriopathy. A scalable, minimally invasive mouse model that reproduces this hemodynamic trigger is needed to enable mechanistic dissection in a genetically tractable system.

An ultrasound-guided transcatheter aortopulmonary shunt procedure was developed to create ductus-like communication between the aortic arch and pulmonary artery. Shunt formation and patency were confirmed by B-mode echocardiography with color and pulsed-wave Doppler. Hemodynamics and right ventricular function were assessed by transthoracic echocardiography and closed-chest micromanometer catheterization at 1 month after surgery. A subset of animals was analyzed at 14 days for early endothelial plasticity. Bulk RNA sequencing of pulmonary arteries was performed to define transcriptional remodeling associated with shunt-driven disease.

Transcatheter aortopulmonary shunt produced a sustained left-to-right overcirculation with Doppler-confirmed shunt flow, which induced pulmonary artery hypertension with elevated right ventricular systolic pressure, increased pulmonary vascular load, and progressive right ventricular dilation and dysfunction. Histological analyses demonstrated robust pulmonary arterial remodeling, including medial muscularization and thickening, adventitial expansion, and perivascular fibrosis, accompanied by right ventricular cardiomyocyte hypertrophy and increased myocardial fibrosis. Transcriptomic profiling of pulmonary arteries revealed broad differential gene regulation consistent with pulmonary artery hypertension pathobiology, including inflammatory, proliferative, and profibrotic responses and increased mesenchymal/smooth muscle marker expression. Costaining endothelial and mesenchymal markers supported endothelial phenotypic transition within the remodeled pulmonary arterial wall.

Transcatheter aortopulmonary shunt establishes a minimally invasive, reproducible murine model of shunt-driven pulmonary artery hypertension triggered by flow-mediated arteriopathy. This platform provides a versatile tool to interrogate flow-sensing mechanisms and to evaluate therapies targeting both vasoreactivity and structural remodeling in pulmonary artery hypertension.