BMPR2 Preserves Mitochondrial Function and DNA during Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension

Abstract

Summary Mitochondrial dysfunction, inflammation and mutant bone morphogenetic protein receptor (BMPR)2 are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC-deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production and glycolysis, induces mitochondrial fission, and a pro-inflammatory state. These features are recapitulated in PAEC from PAH patients with mutant BMPR2.

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

“…Neither IPAH/HPAH PAEC nor iPSC-EC showed a difference in cell growth when compared with control cells as judged by the WST-8 assay over 7 days in full-serum media (see Figure E5). As in our previous study changes in mitochondrial membrane potential could be detected without a change in proliferation (19).…”

“…For example, differential methylation seems to explain the cell-specific expression of the superoxide dismutase, and the endothelial nitric oxide synthase genes (26,27). Other studies, however, have shown similarities in PAEC and systemic EC dysfunction studied in relation to loss of BMPR2 (19,28), and to PAH in general (29). Here, we provide evidence for the first time that IPAH/HPAH PAEC and iPSC-EC from the same individuals have similar functional impairment related at least in part to reduced BMPR2 and downstream signaling, and gene expression of COL4A2.…”

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

“…Reactivation of the developmental signaling pathways is often associated with abnormal lineage specification and disease pathology in adult tissues. Coordinated Wnt and BMPR2 signaling influence the proliferation and survival of endothelium and smooth muscle during angiogenesis as well as vascular remodeling of the pulmonary circulation (20)(21)(22). We therefore sought to determine how their coordinated signaling in resident lung ABCG2 + mesenchymal precursors regulates pulmonary microvascular homeostasis in vivo and in vitro.…”

Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

“…For example, the inflammatory mediator TNF-α (19), and genetic deficiency of BMPR2 or TopBP1 (20,21) can both promote DNA damage and impair endothelial cell proliferation and survival. Recently, we demonstrated that oxidative stress caused by reoxygenation after hypoxia combined with BMPR2 deficiency induced a mitochondrial DNA deletion, elevated caspase-3/7 activity in PAECs, and impaired reversal of pulmonary hypertension (22).…”