Pulsatile flow dynamics maintain pulmonary artery architecture
Stephen B. Spurgin, Lauren Thai, Tina C. Wan, Christopher P. Chaney, Mitzy A. Cowdin, Surendranath Veeram Reddy, Tarique Hussain, Munes Fares, M. Luisa Iruela-Arispe, Thomas Carroll, Andrew D. Spearman, Ondine Cleaver
Stephen B. Spurgin, Lauren Thai, Tina C. Wan, Christopher P. Chaney, Mitzy A. Cowdin, Surendranath Veeram Reddy, Tarique Hussain, Munes Fares, M. Luisa Iruela-Arispe, Thomas Carroll, Andrew D. Spearman, Ondine Cleaver
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Research Article Cardiology Vascular biology

Pulsatile flow dynamics maintain pulmonary artery architecture

Abstract

Single-ventricle congenital heart disease (SV-CHD) is a uniformly lethal condition requiring the Glenn surgery, which as a side effect eliminates arterial pulsatility and contributes to pulmonary vascular complications. In Glenn patients, we quantified pulsatility loss in each dimension of force (flow, pressure, and stretch) using cardiac catheterization and MRI. To model and investigate the individual impact of each dimension of pulsatility loss on the pulmonary vasculature, we applied isolated pulsatile and non-pulsatile mechanical stimuli to pulmonary artery endothelial cells (ECs) in vitro. We found that each dimension of force triggered distinct transcriptional responses, revealing force-specific regulation of structural and signaling pathways. Pulsatile stretch uniquely stimulated EC secretion of PDGFB, a key driver of vascular smooth muscle cell (vSMC) recruitment. In a rat Glenn model, loss of pulsatility led to vascular wall thinning, loss of EC PDGFB, and reduced activation of smooth muscle PDGFBRβ, confirming in vivo relevance. Our findings uncover a mechanistic link between endothelial stretch sensing and PDGFB-mediated EC-vSMC crosstalk, essential for maintaining pulmonary artery architecture. Clinically, these insights suggest that restoring or mimicking pulsatile forces may help preserve vascular integrity and prevent remodeling in patients with SV-CHD.

Authors

Stephen B. Spurgin, Lauren Thai, Tina C. Wan, Christopher P. Chaney, Mitzy A. Cowdin, Surendranath Veeram Reddy, Tarique Hussain, Munes Fares, M. Luisa Iruela-Arispe, Thomas Carroll, Andrew D. Spearman, Ondine Cleaver

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Figure 1

Loss of pulsatility in 3 dimensions within Glenn pulmonary arteries.

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Loss of pulsatility in 3 dimensions within Glenn pulmonary arteries. (A)...
(A) Diagrams of representative normal and Glenn cardiopulmonary anatomy. Red box highlights location of force pulsatility measurements at the right pulmonary artery (RPA). LPA, left pulmonary artery; SVC, superior vena cava. (B) Hemodynamic forces act on ECs in 3 dimensions: laminar shear stress (LSS)/flow (blue), pressure (orange), and circumferential stretch (green). Figure created in Biorender. (C) Outline of data collection method for each dimension of hemodynamic force. (D) Example pressure waveforms from the RPA of normal and Glenn patients. Electrocardiogram shown in red for correlation to cardiac cycle. (E) Variation in flow velocity of the proximal RPA measured by cardiac MRI throughout a cardiac cycle from systole (start) to end-diastole (end). Variability in length of time for each patient reflects the variable heart rate within each participant. (F) Cardiac MRI velocity–encoded phase-contrast images, with color showing velocity of blood flow out of the plane of the image slice. Dotted orange line shows RPA border. RPA diameter increases during systole in a normal patient but does not increase during systole in Glenn patient. (G) Quantification of pulse difference of each dimension of force, obtained during combined cardiac catheterization and cardiac MRI of normal (n = 20) and Glenn (n = 20) patients, demonstrating loss of pulsatility in the Glenn. Circumference change (%) was calculated from baseline in diastole. ****P ≤ 0.0001 by unpaired, 2 tailed Student’s t test with Welch’s correction.