Endothelial-smooth muscle microgauges for modeling pulmonary arterial vasoregulation

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease for which there is no cure. The pathogenesis of PAH involves endothelial dysfunction and dysregulation of vascular tone, resulting in progressively narrowing pulmonary arteries that increase hemodynamic resistance and blood pressure. The development of effective therapeutics for PAH is hindered by limitations to animal models and a lack of humanized in vitro systems that recapitulate endothelial-dependent regulation of smooth muscle cell contractility. Here, we microfabricated pulmonary artery smooth muscle microgauges (PA-SMUGs) that enable quantification of contractile forces generated by human pulmonary arterial smooth muscle cells (PASMCs) within microtissues that contain a functional monolayer of pulmonary arterial endothelial cells (PAECs). PA-SMUGs demonstrate PAEC-dependent vasorelaxation and respond to Treprostinil, a clinically approved PAH therapy. This platform, which establishes a high-throughput method for quantifying EC-dependent vasorelaxation, will facilitate mechanistic studies into the role of PAEC-PASMC crosstalk in PAH pathogenesis and enable screening for novel therapeutics to improve PAH outcomes and hypertensive diseases more broadly.