A transcriptional analysis of BMPR2 loss and BMP9-induced hyperproliferation in endothelial cells: Implications for pulmonary arterial hypertension
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Authors
VandenBroek, Michael Martin Anthony
Date
2024-06-03
Type
thesis
Language
eng
Keyword
BMPR2 , Pulmonary arterial hypertension , Endothelial , Proliferation , BMP9 , Smad signalling , Translation , Stress granule
Alternative Title
Abstract
Background: Pulmonary arterial hypertension (PAH) is a disease of occlusive vascular remodelling, characterized by excessive proliferation of the cells of the lung microvasculature. Genetic, pathological, and experimental evidence all point to endothelial cell dysfunction as the main factor promoting disease pathogenesis. In particular, PAH is associated with mutations in BMPR2, the gene encoding the bone morphogenetic protein (BMP) type II receptor (BMPR-II). Recent work has shown that while BMP9 suppresses cell growth in healthy cells, cells lacking BMPR-II have a hyperproliferative response to BMP9, although the molecular machinery driving this phenotype is not yet understood. Additionally, although BMPR2 loss is known to effect endothelial function via several noncanonical mechanisms, its impact on the endothelial circular RNAs (circRNAs) profile, and their contribution to disease, are not clear.
Results: Through RNA sequencing analysis of healthy endothelial cells and those lacking BMPR2, in the presence and absence of BMP9, new mediators of the endothelial response to BMP9 with BMPR2 loss have been identified. These include PALD1, RP11-322e11.5, and N4BP3, the latter of which encodes a disease relevant, novel regulator of BMP9-mediated canonical signalling. In addition, this sequencing dataset was used to identify two novel circRNAs derived from the BMPR2 gene, including circ3218 and circ5078, the latter of which was discovered to regulate endothelial proliferation, stress, and translational responses via an interrelation with the function of linear BMPR2 RNAs.
Conclusions: This study has identified several novel mechanisms by which the BMPR2 gene regulates to endothelial function, both at the RNA and protein level. These findings are critical to the understanding of the role of BMPR2 in PAH, especially considering the recent success of PAH therapies that target the genetic causes of disease.