BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the BMPR2 gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.

Biology and function of pericytes in the vascular microcirculation

“…Vasoconstriction and in situ thrombosis, which impair lung flexibility and the hemodynamics of the vascular system, result in right ventricular dysfunction, myocardial cell injury, and death. [54][55][56][57][58][59][60] Pericytes are known to influence the progression of PH through multiple mechanisms and play an important role in regulating baseline cellular activities involved in maintaining homeostasis. 61 Also, pericytes are supportive mesenchymal cells, which can differentiate into numerous cell types, including SMCs.…”

“…The pathogenesis of PH results from the excessive proliferation of vascular wall cells (including ECs, SMCs, and fibroblasts) leading to pulmonary endothelial dysfunction and smooth muscle hypertrophy, and inflammation infiltration resulting in progressive remodeling of the peripheral pulmonary artery. Vasoconstriction and in situ thrombosis, which impair lung flexibility and the hemodynamics of the vascular system, result in right ventricular dysfunction, myocardial cell injury, and death 54‐60 …”

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

“…In the pulmonary vasculature, BMPR2 has a high expression in the endothelium, and less in the PASMC [ 40 ]. BMP signaling occurs through a heterodimeric complex of two type-1 receptors and two type-2 receptors.…”

“…Pathogenic mutations in all the main domains of BMPR2 have been documented, and, although at a lower frequency, mutations in other related genes such as BMP9 , BMP10 , ALK , SMAD8/9 or endoglin have been observed in some studies, highlighting the importance of this axis for the pulmonary vasculature homeostasis [ 44 , 45 , 46 , 47 ]. Dysregulation of the BMP pathway leads to an imbalance between anti-proliferative and pro-proliferative routes ( Figure 2 A): decreased BMPR2 activity (anti-proliferative effects) causes reduced BMP9/10-mediated signaling, and thus increased apoptosis and reduced endothelial barrier integrity [ 40 ]. This promotes the production of activin A, growth differentiation factors (GDF) 8 and 11 that bind to the ALK (type-1 receptor)—activin receptor type IIA (ActRIIA, type-2 receptor) complex (from the TGFβ superfamily) and activate the pro-proliferative Smad2/3 pathway.…”

“…The transcription factor PPARγ, which is a downstream target of BMPR2, plays a key role in glucose homeostasis (and vascular remodeling), and its decrease in PAH is thought to be a key element among the factors involved in the metabolic alterations of this disease [ 73 ]. Derangements in the fatty acid metabolism have also been observed, with right ventricular steatosis and lipotoxicity from triglyceride metabolites and reactive oxygen species, possibly due to increased fatty acid delivery to the ventricle, fatty acid synthesis, and reduced oxidative mitochondrial capacity [ 40 , 77 ]. Interestingly, mitochondrial products could play a regulatory role of transcription factors and epigenetic mechanisms [ 34 ].…”