Extract
It has been over 20 years since the discovery of heterozygous germline mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) in families with pulmonary arterial hypertension (PAH) [1, 2]. Much has been learned since then regarding how mutations in BMPR2 cause PAH, although many questions remain unanswered. Mechanistically, loss of BMPR2 signalling in vascular cells, and particularly endothelial cells, greatly increases the likelihood of initiating the characteristic vascular pathology seen in the lungs of patients with PAH [3]. Although asymptomatic carriers of BMPR2 mutations are at markedly increased risk of developing PAH (at least 10 000-fold greater risk than non-carriers), one of the features of BMPR2 mutations is that they exhibit reduced penetrance [4]. In other words, carriers of BMPR2 mutations do not inevitably develop PAH. This is of great interest scientifically because it implies the need for additional “triggering” factors in the context of BMPR2 mutations that are required in order for disease to develop. The potential triggering factors identified to date come from in vitro studies of patient-derived cells and in genetically modified mice [5, 6]. Inflammation-induced injury seems to stimulate a greater degree of pulmonary vascular remodelling in BMPR2 deficient mice than in wild-type littermates, and BMPR2 deficient mice possess an exaggerated inflammatory response to injury [7]. This amplification of certain inflammatory pathways may initiate and propagate the vascular changes. In addition, the presence of a BMPR2 mutation in pulmonary vascular endothelial cells increases susceptibility to apoptosis and increases vascular permeability in response to injury [8–10]. These extrinsic factors act to further suppress BMPR2 signalling, or exacerbate a dysfunctional endothelium already primed by the presence of mutation.
Abstract
Pulmonary hypertension physicians must embrace this new and exciting aspect of clinical care of PAH patients for the benefit of our present and future patients https://bit.ly/3pf7GhG
Footnotes
Conflict of interest: N.W. Morrell reports grants and personal fees from Morphogen-IX, outside the submitted work.
Support statement: This work was supported by the British Heart Foundation and the National Institute for Health Research. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received January 29, 2021.
- Accepted January 30, 2021.
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