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 4

PDGFB expression in human lungs is EC specific, stretch induced, and stimulates vSMC proliferation.

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PDGFB expression in human lungs is EC specific, stretch induced, and sti...
(A) Left: Cell-specific gene expression in human lung tissue was analyzed within the LungMAP single-cell RNA-seq data (347,970 cells). Right: Expression of PDGFB is high in ECs, with its receptor PDGFRβ found in pericytes and vSMCs. AEC, arterial endothelial cells; AF1, alveolar fibroblasts; AF2, adventitial fibroblast; AM, alveolar macrophage; IM, interstitial macrophage; LEC, lymphatic endothelial cells; NK, natural killer cells; SVEC, systemic vein endothelial cells; VEC, pulmonary venous endothelial cells. (B) Different human cell lines comprising the primary components of a blood vessel (endothelium, smooth muscle, fibroblasts) were exposed to pulsatile uniaxial 10% stretch at 1 Hz and only ECs secreted PDGFB into the media (as measured by ELISA). (C) Conditioned media from HPAECs placed under either 15 dyn/cm2 flow or 10% stretch at 1 Hz for 48 hours were assayed for PDGF-BB by ELISA, showing a 5-fold greater induction of PDGFB by stretch. (D) PDGFB measured by ELISA shows a significant reduction in plasma PDGFB from pulmonary artery to pulmonary vein (pulmonary capillary wedge sample, PCW) in plasma of Glenn patients compared with normal patients. (E) Left: Conditioned media from cultured HPAECs under stretch or static conditions were added to serum-starved (6 hours) PASMCs with or without SU-16f (a potent and selective small-molecule inhibitor of PDGFRβ), and EdU incorporation was measured after 24 hours. Right: Example immunofluorescent staining of PDGFB production by stretched ECs used for this experiment. (F) Left: EdU incorporation was greatest in PASMCs treated with stretched EC media, but the proliferative stimulus was blocked by SU-16f. Right: Example immunofluorescent staining of EdU incorporation by PASMCs. (E and F) Scale bar: 50 μm. *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001 by unpaired, 2-tailed Student’s t test (B and C) or unpaired, 2-tailed Student’s t test with Welch’s correction (D and F).