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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