Pulmonary hypertension (PH) is a complex pulmonary vascular condition with increasing global prevalence and with particularly severe forms, such as pulmonary arterial hypertension (PAH), that are often fatal. In PAH, remodeling in diseased pulmonary arteries places an increasing hemodynamic burden on the right ventricle, leading to right ventricular failure, multiorgan dysfunction, and death. Current PH medications primarily target three major vasodilatory pathways (nitric oxide, endothelin, and prostacyclin signaling) but do not target the elusive upstream molecular origins of PH. Thus, they neither prevent nor reverse disease. Hence, there is a great need to identify the upstream molecular triggers of disease and apply those discoveries to clinical benefit. However, the pathogenesis of PH is complex and multifactorial. It involves both multiple vascular and nonvascular cell types and depends on several pathogenic events (ie, genetic susceptibility, hypoxia, inflammation, viral infection, DNA damage, and shear stress, among others) for disease manifestation and progression (1, 2). An inability to fully unravel these molecular complexities has led to multiple clinical challenges in developing both new diagnostics and therapeutics for this disease.

Discoveries have identified the dysregulation of microRNAs (miRNAs) as integral events that shape the development and progression of PH (3). miRNAs are small noncoding RNA molecules that negatively regulate gene expression and perform pervasive regulatory functions in all aspects of biology, both in the animal and plant kingdoms (4). A number of key reports have implicated miRNAs in a wide range of pulmonary vascular processes, spanning pulmonary vascular development, physiology, and disease and leading to speculation on their usefulness in clinical diagnosis and prognosis. Yet, we still are at the inception of this growing field of study, and a number of challenges remain in applying this biology to clinical practice. In this review, we discuss both the fundamental biology of miRNAs in PH and the translational potential and obstacles in their development as novel biomarkers and direct therapeutics.