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 5

Loss of PDGFB in pulmonary endothelium and p-PDGFRβ in pulmonary vascular smooth muscle of rats after Glenn surgery.

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Loss of PDGFB in pulmonary endothelium and p-PDGFRβ in pulmonary vascula...
(A) Left: Representative immunofluorescent (IF) staining of pulmonary arterioles from left lung of sham- and Glenn-operated rats. Pulmonary arterioles were identified by presence of VECAD (cyan) and αSMA (pink), near lung periphery, and less than 50 μm in diameter. Scale bars: 5 μm. Right: Quantification of PDGFB IF staining in pulmonary arteriolar and capillary ECs in sham- (n = 91 arteriolar ECs, n = 74 capillary ECs) and Glenn-operated (n = 89 arteriolar ECs, n = 62 capillary ECs) rats demonstrates significant loss of EC-derived PDGFB in the Glenn lung. Five vessels each from the left lung of 3 sham and 3 Glenn rats were analyzed. (B) Left: Representative IF staining of proximal pulmonary arteries from left lung of sham- and Glenn-operated rats for p-PDGFRβ (yellow). Pulmonary arteries were identified as >100 μm in diameter, having ECs (CDH5, green), bounded by vascular smooth muscle (αSMA, pink), and by similarity in size and proximity to the largest airway in slices near the hilum of the lung. Scale bars: 5 μm. Right: Quantification of mean p-PDGFRβ staining intensity in αSMA+ cells (using the αSMA signal to mask the p-PDGFRβ channel) in the subendothelial medial layer in sham and Glenn rats (n = 3 vessels for each of n = 3 sham and n = 3 Glenn rats). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 by unpaired, 2-tailed Student’s t test with Welch’s correction (A and B).