Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers.
نویسندگان
چکیده
In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration, and angiogenesis compared to UMC-iPSC-ECs and control cells. The "rescued" phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and was independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.
منابع مشابه
Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance.
BACKGROUND Bone morphogenic protein receptor 2 (BMPR2) gene mutations are the most common cause of heritable pulmonary arterial hypertension. However, only 20% of mutation carriers get clinical disease. Here, we explored the hypothesis that this reduced penetrance is due in part to an alteration in BMPR2 alternative splicing. METHODS AND RESULTS Our data showed that BMPR2 has multiple alterna...
متن کاملCytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension.
The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was...
متن کاملPhysiologic and molecular consequences of endothelial Bmpr2 mutation
BACKGROUND Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown. METHODS In vivo experiments were performed on adult mice with conditional endothelial-spec...
متن کاملAbsence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension
BACKGROUND Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missens...
متن کاملSMAD1 deficiency in either endothelial or smooth muscle cells can predispose mice to pulmonary hypertension.
A deficiency in bone morphogenetic protein receptor type 2 (BMPR2) signaling is a central contributor in the pathogenesis of pulmonary arterial hypertension (PAH). We have recently shown that endothelial-specific Bmpr2 deletion by a novel L1Cre line resulted in pulmonary hypertension. SMAD1 is one of the canonical signal transducers of the BMPR2 pathway, and its reduced activity has been shown ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Cell stem cell
دوره 20 4 شماره
صفحات -
تاریخ انتشار 2017