The Role of Bone Morphogenetic Protein Receptor Type 2 (BMPR2) and the Prospects of Utilizing Induced Pluripotent Stem Cells (iPSCs) in Pulmonary Arterial Hypertension Disease Modeling

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR), causing right ventricular hypertrophy and ultimately death from right heart failure. Heterozygous mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are linked to approximately 80% of hereditary, and 20% of idiopathic PAH cases, respectively. While patients carrying a BMPR2 gene mutation are more prone to develop PAH than non-carriers, only 20% will develop the disease, whereas the majority will remain asymptomatic. PAH is characterized by extreme vascular remodeling that causes pulmonary arterial endothelial cell (PAEC) dysfunction, impaired apoptosis, and uncontrolled proliferation of the pulmonary arterial smooth muscle cells (PASMCs). To date, progress in understanding the pathophysiology of PAH has been hampered by limited access to human tissue samples and inadequacy of animal models to accurately mimic the pathogenesis of human disease. Along with the advent of induced pluripotent stem cell (iPSC) technology, there has been an increasing interest in using this tool to develop patient-specific cellular models that precisely replicate the pathogenesis of PAH. In this review, we summarize the currently available approaches in iPSC-based PAH disease modeling and explore how this technology could be harnessed for drug discovery and to widen our understanding of the pathophysiology of PAH.

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“…BMPR2 is a gene encoding the bone morphogenetic protein receptor type II, which plays a crucial role in the signaling pathway of the bone morphogenetic protein (BMP) family. 15 BMPR2 mutations have been associated with the development of pulmonary arterial hypertension (PAH). BMPR2 mutations are present in approximately 70% of individuals with familial PAH and in approximately 15% of individuals with sporadic PAH.…”

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“…What this also means is that patientspecific differences in disease susceptibility due to genetic background, for example the effect of accompanying SNPs, can be modelled in the absence of the confounding "main" mutation. Several studies have used iPSCs and derived vascular cells-VSMCs, pericytes and ECs-to model a variety of vascular diseases including, pulmonary arterial hypertension (112)(113)(114)(115)(116)(117)(118)(119), Hutchison-Gilford progeria (120)(121)(122)(123)(124), atherosclerosis (47,125,126), neurodegenerative cerebro-vascular conditions like Moyamoya disease (127)(128)(129)(130)(131), CADASIL (132)(133)(134)(135), diabetes and its associated conditions (136-138).…”

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“…[77][78][79] Pulmonary hypertension due to HIF2A gain of function variants and BMPR2 pathogenic variants have also been modeled with hiPSC-SMCs. [80][81][82] Although most studies using hiPSC-SMCs as a disease model are attempting to model a monogenic disorder where the pathogenic variant is known, a few studies have used these cells to model more common disease processes. One study used hiPSC-SMCs derived from patients with hypertension with the stated eventual goal being to screen the responsiveness of patient-specific cells to different antihypertensive medications, which would optimize personalized treatments to control blood pressure.…”

“…77–79 Pulmonary hypertension due to HIF2A gain of function variants and BMPR2 pathogenic variants have also been modeled with hiPSC-SMCs. 80–82…”