Hypoxia‐induced pulmonary hypertension upregulates eNOS and TGF‐β contributing to sex‐linked differences in BMPR2^+/R899X mutant mice

Abstract

Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) and endothelial nitric oxide synthase (eNOS) have been largely implicated in the pathogenesis of pulmonary arterial hypertension (PAH); a life‐threatening cardiopulmonary disease. Although the incident of PAH is about three times higher in females, males with PAH usually have a worse prognosis, which seems to be dependent on estrogen‐associated cardiac and vascular protection. Here, we evaluated whether hypoxia‐induced pulmonary hypertension (PH) in humanized BMPR2 +/R899X loss‐of‐function mutant mice contributes to sex‐associated differences observed in PAH by altering eNOS expression and inducing expansion of hyperactivated TGF‐β‐producing pulmonary myofibroblasts. To test this hypothesis, male and female wild‐type (WT) and BMPR2 +/R899X mutant mice were kept under hypoxic or normoxic conditions for 4 weeks, and then right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) were measured. Chronic hypoxia exposure elevated RVSP, inducing RVH in both groups, with a greater effect in BMPR2 +/R899X female mice. Lung histology revealed no differences in vessel thickness/area between sexes, suggesting RVSP differences in this model are unlikely to be in response to sex‐dependent vascular narrowing. On the other hand, hypoxia exposure increased vascular collagen deposition, the number of TGF‐β‐associated α‐SMA‐positive microvessels, and eNOS expression, whereas it also reduced caveolin‐1 expression in the lungs of BMPR2 +/R899X females compared to males. Taken together, this brief report reveals elevated myofibroblast‐derived TGF‐β and eNOS‐derived oxidants contribute to pulmonary microvascular muscularization and sex‐linked differences in incidence, severity, and outcome of PAH.

Schistosomiasis-associated pulmonary hypertension unveils disrupted murine gut–lung microbiome and reduced endoprotective Caveolin-1/BMPR2 expression

“…EC injury in IPAH and animal models of hypoxia-induced PH is associated with Cav-1 phosphorylation and depletion via shedding of extracellular vesicles into the circulation (13). Despite previous studies' findings on EC-Cav-1/ BMPR2 depletion as an important switch towards endothelial dysfunction (21,31,35), more specific information about what triggers the process remains unclear. Here, we observed that pathogens can contribute to EC-Cav-1/BMPR2 depletion and initiate Sch-PAH.…”

“…Indeed, BMPR2 deficiency is known to promote cell death, endothelial-to-mesenchymal transition (endoMT), and abnormal proliferation of pulmonary vascular cells, including ECs, which contribute to the severe pulmonary vascular remodeling observed in several subgroups of PAH ( 29 – 33 ). Moreover, it has been shown that heterozygous Bmpr2 +/− mice have increased S. mansoni egg translocation in the lungs via enlarged hepatic sinusoids ( 34 ), and Bmpr2 +R899X loss-of-function mutant mice develop “spontaneous” PH, reinforcing the crucial role of this signaling pathway in the development of PAH, including the infectious disease ( 35 ).…”

Understanding pulmonary hypertension: the need for an integrative metabolomics and transcriptomics approach

“…PAH patients are found to be associated mostly with altered bone morphogenetic protein receptor type 2 (BMPR2) (a transmembrane serine/threonine kinase family gene), 58,59 G protein coupled receptor (GPCR) related genes (a large family encoding surface receptors), 60 pyruvate dehydrogenase kinase 4 (PDK4) (protein kinase family) 61 and transforming growth factor beta (TGF-b) signaling pathways. 62 Several studies have indicated an association between these genes and hypoxic pathways, [63][64][65] which is one of the hallmarks of PH. The primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs).…”

“…TGF-b is found to be highly upregulated in both medial and intimal layers of remodelled pulmonary vessels. 63,69 The importance of both BMPR2 and TGF-b has been implicated in PH pathophysiology.…”