Engineered pulmonary artery tissues for measuring contractility, drug testing and disease modelling

Abstract

Background and Purpose

Vasoreactivity of pulmonary arteries regulates blood flow through the lungs. Excessive constriction of these vessels contributes to pulmonary arterial hypertension (PAH), a progressive and incurable condition, resulting in right heart failure. The search for new and improved drug treatments is hampered by laboratory models that do not reproduce the vasoactive behaviour of healthy and diseased human arteries.

Experimental Approach

We have developed an innovative technique for producing miniature, three-dimensional arterial structures that allow proxy evaluation of human pulmonary artery contractility. These “engineered pulmonary artery tissues” or “EPATs” are fabricated by suspending human pulmonary artery vascular smooth muscle cells (VSMCs) in fibrin hydrogels between pairs of silicone posts, located on custom-made racks, in 24-well culture plates.

Key Results

EPATs exhibit rapid, robust and reproducible contraction responses to vasoconstrictors (KCl, ET-1, U46619) as well as relaxation responses to clinically approved PAH vasodilatory drugs that target several signalling pathways, such as bosentan, epoprostenol, selexipag and imatinib. EPATs composed of pulmonary artery VSMCs from PAH patients exhibit enhanced contraction to vasoconstrictors and relaxation in response to vasodilators. We also demonstrate the incorporation of endothelial cells into EPATs for the measurement of endothelium-dependent dilatory responses.

Conclusion and Implications

We demonstrate the capacity and suitability of EPATs for studying the contractile behaviour of human arterial cells and preclinical drug testing. This novel biomimetic platform has the potential to dramatically improve our understanding and treatment of cardiovascular disease.