Targeting the Prostacyclin Pathway: Beyond Pulmonary Arterial Hypertension

Abstract

Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI₂) and its analogs have raised much pharmacological interest. In this review we detail how the PGI₂ signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI₂-thromboxane A₂ (TXA₂) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI₂ analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI₂ pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers.

Keywords: multidrug resistance protein 4; peroxisome proliferator-activated receptors; prostacyclin; vascular homeostasis.