Endothelial-targeted CD39 prevents Toxin-induced Pulmonary Hypertension Mice

Disruption of the pulmonary endothelium by drugs, toxins, viruses (e.g., COVID-19), or bacterial sepsis can cause acute pulmonary vasculopathy leading to pulmonary hypertension and consequential heart failure. CD39 is a membrane-anchored ecto-enzyme expressed on endothelial cells (EC), integral in maintaining the antithrombotic profile of the endothelium. This ecto-enzyme works in concert with CD73 to hydrolyze both eATP (pro-inflammatory) and ADP (pro-thrombotic) ultimately to adenosine, which is anti-inflammatory, vasodilatory, and antithrombotic. CD39 activity and adenosine signalling are disrupted in idiopathic pulmonary arterial hypertension (PAH). In this work, we explored the efficacy of endothelial cell-targeted delivery of CD39 to prevent the development of acute toxin-induced PAH in a mouse model.

We generated a novel therapeutic anti-VCAM-CD39 containing an scFv recognising VCAM-1 (a receptor expressed on activated EC) fused to the soluble form of extracellular human CD39. In a mouse model of endothelial cell-toxin-induced PAH, we show that a single administration of anti-VCAM-CD39 (0.4 mg/kg IV) prevented the development of PAH— as reflected in the preservation of right ventricular systolic pressures and the absence of right ventricular hypertrophy at day 10 when compared with controls. This protection is conferred by multiple mechanisms: IL-10-driven potentiation of heme oxygenase (HO)-1, a known inhibitor of smooth muscle proliferation; VCAM-1 blockade reduces leukocyte adhesion to the endothelium; and cytoprotective effects through adenosine signalling. Thus, anti-VCAM-CD39 is a novel bifunctional therapeutic strategy for PAH.