Pulmonary arterial hypertension (PAH) encompasses a group of syndromes involving elevations in pulmonary artery pressures caused by remodeling of pulmonary arteriole structure. PAH is defined as a mean pulmonary artery pressure of (PAP) >20 mmHg with a pulmonary capillary wedge pressure (PCWP) ≤15 and pulmonary vascular resistance (PVR) ≥ 3 Wood Units (WU) or PVRi > 3 WU ∙m2 in children. PAH is further classified into Heritable PAH (HPAH), PAH associated with other conditions or toxin/drug exposures, and Idiopathic Pulmonary Arterial Hypertension (IPAH) [1] IPAH recognizes PAH without an associated cause or affected relative and is more common in contrast to HPAH in which at least one affected relative or accountable gene mutation is recognized. We now recognize that a number of patients with IPAH have later been identified to have a genetic cause and reclassified as HPAH in the absence of affected family members often attributed to variable penetrance or de novo mutation [2] Overall age-standardized prevalence of PAH in 2021 was estimated to be 2.28 cases per 100,000 persons, with an estimated 8.24 disability-adjusted life years (DALYs) contributed per 100,000 persons [3] Despite the advent of disease-specific therapies, transplant free survival with PAH continues to be unacceptably high with an estimated 1 and 3-year survival of 91.4 and 76.9 among adults [4] Earlier onset PAH in children often present with a complex and more severe clinical course [5] Current management of PAH involves vasodilators in responsive patients and may include invasive interventions such as atrial septostomy, systemic to pulmonary artery shunting, or lung transplantation in those non-responsive to medical therapy. PAH is also a significant contributor to worldwide healthcare costs, ranging from $2476 to $11,875 per patient per month on average [6] These facts highlight the continued need for a better understanding of the pathogenesis of PAH and development of better treatments.

Genetic mutations have been implicated in IPAH and HPAH. The most common and studied gene known to be involved is bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor β (TGF-β) family. It has been observed that mutations in BMPR2 cause widespread metabolic dysfunction, glycolytic reprogramming, defective iron handling, and changes in estrogen pathways through augmentation of miRNA expression and activity, contributing to uncontrolled cellular proliferation and apoptosis resistance [7] Correspondingly, promising therapeutics targeting the TGF-β/BMP pathway have been studied, with rescuing of bone morphogenic protein (BMP) signaling in murine models shown to inhibit pulmonary vascular proliferation [8] Other genes have also been found to be altered in IPAH, including caveolin-1 (CAV1), T-box transcription factor 4 (TBX4), and other components of signaling downstream of BMPR2 such as SMAD1, SMAD4, and SMAD9 [9] Overall however, the genetic background and interplay between various genes has yet to be comprehensively understood.