The pathophysiology of vascular remodeling in pulmonary hypertension

Pulmonary hypertension (PH) represents a grave and relentless medical condition, characterized clinically by elevated pulmonary arterial pressure and augmented pulmonary vascular resistance (PVR). This pathophysiological state inevitably progresses to the development of right ventricular (RV) hypertrophy (RVH), culminating in RV failure, and ultimately, mortality. Moreover, PH could

be a confounding complication of chronic lung pathology particularly secondary to interstitial lung disease (ILD), including its severe type- Idiopathic pulmonary fibrosis (IPF). The primary driver of increased PVR in ILD-PH, similarly as in other PH subtypes, is pulmonary vascular remodeling, a complex process involving various cells in pulmonary arterial wall. However, the progression of

PH from ILD remains largely unknown. Recently, the first inhaled vasoactive drug-treprostinil was approved for treating ILD-PH. However, concerns about its potential side effects and high costs highlight the urgent need for innovative strategies to manage ILD-PH. Unfortunately, there is currently no treatment specifically designed to target vascular remodeling in ILD-PH.

Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is highly expressed in the lung; however, our understanding about its role in lung diseases is very limited. BMPER is a secreted regulator that regulates vascular development via fine-tuning the BMP pathway. BMP plays a pivotal role in the development of pulmonary arterial hypertension. Animal models

targeting BMP pathway components (i.e. BMPR2, Gremlin1) also illuminate their regulatory functions in other forms of PH, including that associated with ILD. However, the role of BMPER has not been studied in any forms of PH. In this study, we will define a new and lung-specific paracrine regulatory mechanism mediated via BMPER for vascular remodeling during the

progression of ILD-PH. First, we will define the transcriptional regulation of BMPER during the progression of ILD-PH. Next, we will establish mechanisms governing BMPER regulation of pulmonary vascular remodeling. Last, we will assess the tissue-specific BMPER expression in the development of vasculopathy in patients with ILD-PH.