BMPR2
Bone morphogenetic protein receptor type-2 precursor (EC 2.7.11.30) (BMP type-2 receptor) (BMPR-2) (Bone morphogenetic protein receptor type II) (BMP type II receptor) (BMPR-II) [PPH1]
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Aging has detrimental effects on the ovary, such as a progressive reduction in fertility and decreased hormone production, that greatly reduce the quality of life of women. Thus, the current study was undertaken to investigate whether human placenta-derived mesenchymal stem cell (hPD-MSC) treatment can restore the decreases in folliculogenesis and ovarian function that occur with aging. Acclimatized 52-week-old female SD rats were randomly divided into four groups: single hPD-MSC (5 × 10 ) therapy, multiple (three times, 10-day intervals) hPD-MSC therapy, control (PBS), and non-treated groups. hPD-MSC therapy was conducted by tail vein injection into aged rats. The rats were sacrificed 1, 2, 3, and 5 weeks after the last injection. hPD-MSC tracking and follicle numbers were histologically confirmed. The serum levels of sex hormones and circulating miRNAs were detected by ELISA and qRT-PCR, respectively. TGF-β superfamily proteins and SMAD proteins in the ovary were detected by Western blot analysis. We observed that multiple transplantations of hPD-MSCs more effectively promoted primordial follicle activation and ovarian hormone (E and AMH) production than a single injection. After hPD-MSC therapy, the levels of miR-21-5p, miR-132-3p, and miR-212-3p, miRNAs associated with the ovarian reserve, were increased in the serum. Moreover, miRNAs (miR-16-5p, miR-34a-5p, and miR-191-5p) with known adverse effects on folliculogenesis were markedly suppressed. Importantly, the level of miR-145-5p was reduced after single- or multiple-injection hPD-MSC therapy, and we confirmed that miR-145-5p targets Bmpr2 but not Tgfbr2. Interestingly, downregulation of miR-145-5p led to an increase in BMPR2, and activation of SMAD signaling concurrently increased primordial follicle development and the number of primary and antral follicles. Our study verified that multiple intravenous injections of hPD-MSCs led to improved ovarian function via miR-145-5p and BMP-SMAD signaling and proposed the future therapeutic potential of hPD-MSCs to promote ovarian function in women at advanced age to improve their quality of life during climacterium.
Keywords
- Aging
- Follicular development
- Hormone biosynthesis
- Primordial follicle activation
- Stem cell therapy
- miR-145
Human mesenchymal cells can become pluripotent by the addition of Yamanaka factors OCT3/4, SOX2, c-MYC, KLF4. We have recently reported that centenarians overexpress BCL-xL, which has been shown to improve pluripotency; thus, we aimed to determine the expression of pluripotency-related genes in centenarians. We recruited 22 young, 32 octogenarian, and 47 centenarian individuals and determined the mRNA expression of Yamanaka factors and other stemness-related cell surface marker genes (VIM, BMP4, NCAM, BMPR2) in peripheral blood mononuclear cells by reverse transcription polymerase chain reaction. We found that centenarians overexpress OCT3/4, SOX2, c-MYC, VIM, BMP4, NCAM, and BMPR2, when compared with octogenarians (p < .05). We further tested the functional role of BCL-xL in centenarians' ability to express pluripotency-related genes: lymphocytes from octogenarians transduced with BCL-xL overexpressed SOX2, c-MYC, and KLF4. We conclude that centenarians overexpress Yamanaka Factors and other stemness-related cell surface marker genes, which may contribute to their successful aging.
MeSH Terms
- Adult
- Age Factors
- Aged, 80 and over
- Aging
- Cells, Cultured
- Cohort Studies
- Female
- Gene Expression Regulation
- Humans
- Leukocytes, Mononuclear
- Male
- Membrane Proteins
- Pluripotent Stem Cells
Keywords
- Healthy aging
- Longevity
- Pluripotency
- Stemness
During ovarian follicle growth, local cellular interactions are essential for oocyte quality acquisition and successful fertilization. While cumulus cells (CCs) nurture oocytes, they also deliver oocyte-secreted factors (OSFs) that activate receptors on CCs. We hypothesized that disturbance of those interactions contributes to age-related lower reproductive success in women submitted to assisted reproductive technology treatments. Women aged 27-48, without recognized personal reproductive disorder, were enrolled in the study and divided in <35- and ≥35-year-old groups. CCs collected upon follicle aspiration were processed for immunocytochemistry and RNA extraction. The expression patterns of OSF receptors BMPR2, ALK 4, ALK5, and activin receptor-like kinase (ALK6) were studied. Independently of age, receptors were found mostly in the cell periphery. The quantitative assay revealed that in older women, BMPR2, ALK 4, and ALK6 were all significantly decreased, whereas ALK5 was slightly increased. Female age imparts an effect on the expression of OSF receptors in CCs. The findings indicate that reproductive aging affects the local regulation of signaling pathways mediated by BMPR2, ALK6, and ALK4 receptor activation, suggesting their joint involvement.
MeSH Terms
- Adult
- Anaplastic Lymphoma Kinase
- Bone Morphogenetic Protein Receptors, Type I
- Bone Morphogenetic Protein Receptors, Type II
- Cumulus Cells
- Female
- Fertilization in Vitro
- Gene Expression Regulation, Developmental
- Humans
- Middle Aged
- Oocytes
- Ovarian Follicle
- Protein-Serine-Threonine Kinases
- Receptor Protein-Tyrosine Kinases
- Receptor, Transforming Growth Factor-beta Type I
- Receptors, Transforming Growth Factor beta
- Reproductive Techniques, Assisted
Keywords
- Aging
- Cumulus cells
- Female infertility
- Gene expression
- Growth factors
Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Bone Morphogenetic Protein Receptors, Type II
- Cell Membrane Permeability
- Densitometry
- Endothelial Cells
- Gene Expression Profiling
- Gene Knock-In Techniques
- Growth Differentiation Factor 2
- Heart Ventricles
- Humans
- Hypertension, Pulmonary
- Immunoblotting
- JNK Mitogen-Activated Protein Kinases
- Male
- Mice, Inbred C57BL
- Monocrotaline
- Phosphorylation
- Pulmonary Artery
- Rats
- Rats, Sprague-Dawley
- Systole
- Transcription, Genetic
Children and adults with pulmonary arterial hypertension (PAH) have similarities and differences in their background characteristics, hemodynamics, and clinical manifestations. Regarding genetic background, mutations in BMPR2-related pathways seem to be pivotal; however, it is likely that other modifier genes and bioactive mediators have roles in the various forms of PAH in children and adults. In pediatric PAH, there are no clear sex differences in incidence, age at onset, disease severity, or prognosis but, as compared with adults, syncope incidence, pulmonary vascular resistance, and mean pulmonary artery pressure are higher, and vasoreactivity to acute drug testing is more frequent, among children. Nevertheless, the pharmacokinetic effects of 3 major pulmonary vasodilators appear to be similar in children and adults with PAH. This review focuses on the specific pathophysiologic features of PAH in children.
MeSH Terms
- Adult
- Age Factors
- Age of Onset
- Aging
- Blood Pressure
- Bone Morphogenetic Protein Receptors, Type II
- Child
- Child, Preschool
- Female
- Humans
- Hypertension, Pulmonary
- Infant
- Infant, Newborn
- Male
- Syncope
- Vascular Resistance
- Vasodilator Agents
In a nationwide study, we identified a total of 59 patients diagnosed with primary pulmonary hypertension (PPH) in Finland between the years 1987 and 1999. These data support a minimum estimate for a PPH population prevalence of 5.8 cases/million with an incidence of 0.2-1.3 cases/million/year. The male-to-female ratio among the patients was 1:4, while 7% (4/59) of the PPH probands had a known family history of the disorder. Familial or sporadic PPH showed no geographic clustering to any region of Finland. Sequencing of the coding regions and exon-intron boundaries of the bone morphogenetic protein receptor type 2 (BMPR2) identified heterozygous BMPR2 mutations in 12% (3/26) of the sporadic and 33% (1/3) of the familial patients. All four mutations were different, and two of those have been previously reported in other populations. Pathogenic defects in BMPR2 include a novel missense mutation (c.2696G>C encoding R899P), located within the receptor intracellular cytoplasmic domain whose function has been poorly characterized. Our analysis demonstrates that this mutant, while localizing to the cell surface, does not impact on SMAD-mediated (mothers against decapentaplegic homolog) intracellular signaling, but leads to constitutive activation of the p38(MAPK) pathway. The absence of a founder mutation in a genetically homogeneous population, such as the Finns, suggests that all identified BMPR2 mutations have to be rather young while the ancestral (if any) mutations have been lost either due to repetitive genetic bottlenecks or due to significant negative selection. Hum Mutat 26(2), 1-6, 2005. (c) 2005 Wiley-Liss, Inc.
MeSH Terms
- Adolescent
- Adult
- Bone Morphogenetic Protein Receptors, Type II
- Child
- Child, Preschool
- Family Health
- Female
- Genetic Predisposition to Disease
- Heterozygote
- Humans
- Hypertension, Pulmonary
- Longevity
- Male
- Middle Aged
- Mutation
- Pedigree
- Signal Transduction