The bone morphogenetic protein receptor-1A pathway is required for lactogenic differentiation of mammary epithelial cells in vitro

To understand whether bone morphogenetic protein plays any role in the formation of primordial follicles in the hamster, we examined the temporal and spatial expression of bone morphogenetic protein receptor (BMPR) mRNA and protein in embryonic (E) 13 through postnatal day (P) 15 ovarian cells and a possible regulation by FSH during the formation of primordial follicles on P8. BMPRIA and BMPRII mRNA levels were significantly higher than that of BMPR1B throughout ovary development. BMPRIA and BMPRII mRNA levels increased significantly on E14 and declined by P5 through P6. Whereas BMPRII mRNA increased again by P7, BMPRIA mRNA levels increased through P8 concurrent with primordial follicle formation. In contrast, BMPRIB mRNA levels increased greater than 10-fold on P7-9, with a further 3-fold increase by P10. BMPR proteins were low in the somatic cells and oocytes on E13 but increased progressively during postnatal development. BMPR expression in somatic cells increased markedly on P8. Whereas BMPRII expression declined by P10 and remained steady thereafter, BMPRIA protein expression fluctuated until P15 when it became low and steady. Overall, BMPRIB immunoreactivity also declined by P10 and then remained low in the interstitial cells through P15. FSH antiserum treatment on E12 significantly attenuated receptor mRNA and protein levels by P8, but equine chorionic gonadotropin replacement on P1 reversed the inhibition. Furthermore, FSH in vitro up-regulated BMPR levels in P4 ovaries. This unique pattern of BMPR expression in the oocytes and somatic cells during perinatal ovary development suggests that BMP may play a regulatory role in primordial follicle formation. Furthermore, FSH may regulate BMP action by modulating the expression of its receptors.

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Abstract 445: Endothelial Inflammation and Loss of Bone Morphogenetic Protein Receptor 2 in Oscillatory Shear Stress Model

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.445 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Collins Ezeuka

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Laminar Flow ◽

Bone Morphogenetic Protein ◽

Aortic Endothelial Cells ◽

Bone Morphogenetic Protein Receptor ◽

Endothelial Inflammation ◽

Protein Receptor ◽

Morphogenetic Protein

Background: Bone Morphogenetic Protein Receptor II (BMPR2) plays an unexpected role as a critical anti-inflammatory and anti-atherogenic protein in endothelial cells (ECs) via a reactive oxygen species (ROS) and NFκB-dependent mechanism. Pro-atherogenic stimuli such as disturbed laminar flow, angiotensin II, hypercholesterolemia and the pro-inflammatory cytokine TNFα, significantly downregulate BMPR2 expression in endothelium, while anti-atherogenic stimuli such as laminar flow and statins upregulate BMPR2’s expression in vivo and in vitro. These findings suggest that there may be a common mechanism by which pro-atherogenic factors downregulate BMPR2 expression and that protecting or restoring its expression could be a novel therapeutic approach for prevention and treatment of atherosclerosis. Our preliminary studies have identified microRNAs that possibly play a causative role in the loss of BMPR2, by binding to its 3’-UTR, leading to degradation of BMPR2, endothelial dysfunction, inflammation, and subsequent atherosclerosis. Hypothesis: Rescuing loss of BMPR2 will decrease endothelial inflammation and atherosclerosis Methods: Our in vitro model of disturbed blood flow is characterized by a cone and plate system, wherein mouse aortic endothelial cells are subjected to unidirectional laminar shear (LS 15 dyn/cm2) or oscillatory shear (OS, +/1 5 dyn/cm2 at 1 Hz frequency) for 24 hours. Endothelial cell inflammatory markers, BMPR2, and specific microRNA mRNA transcript fold changes, were then assessed via qPCR. Results: Under oscillatory flow conditions, in our in vitro shear stress system, BMPR2 is lost and mouse aortic endothelial cells acquire an inflammation phenotype, with a corresponding increase in the fold change of mRNA for microRNAs-17, 21, 25, and 181. Conclusion: We have identified microRNAs that may target BMPR2, leading to its degradation, and subsequent onset of endothelial inflammation. Blocking the aforementioned microRNAs may represent a novel therapy in the treatment of endothelial inflammation and subsequent atherosclerosis.

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Abstract 1636: Adverse Effect of Estrogen on Bone Morphogenetic Protein Receptor Signal Pathway in Pulmonary Arterial Endothelial Cells

Circulation ◽

10.1161/circ.118.suppl_18.s_362-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Hiroaki Ichimori ◽

Shigetoyo Kogaki ◽

Hidekazu Ishida ◽

Jun Narita ◽

Toshiki Uchikawa ◽

...

Keyword(s):

Endothelial Cells ◽

Estrogen Receptor ◽

Bone Morphogenetic Protein ◽

Signal Pathway ◽

Bone Morphogenetic Protein Receptor ◽

Protein Receptor ◽

Morphogenetic Protein ◽

Pulmonary Arterial ◽

Arterial Endothelial Cells

Gender differences in the development of Pulmonary Artery Hypertension (PAH) have been documented in both human and animal studies. In human, idiopathic PAH is predominantly a disease of young women in their child-bearing years, which suggests a role of female sex hormones in the pathogenesis of PAH. However, the effect of sex hormones on pulmonary vasculatures and the development of PAH has not been fully understood. Recent researches have revealed genetic predisposition such as BMPR (Bone Morphogenetic Protein Receptor). The aim of the present study is to investigate the effect of β-estradiol (E2) and oxygen concentration upon BMPR signal pathway in pulmonary arterial endothelial cells (PAEC) in vitro. Human and rat PAEC were cultured and we examined the expression of BMPR2, BMP-regulated Smads, and Id1 under 21% or 1% O 2 with BMP2 stimulation. Then, we investigate changes in the expression of these molecules in the presence of E2 with or without estrogen receptor antagonist (ICI 182.780.). First, we confirmed that estrogen receptor α and β were expressed in both PAECs. Second, we demonstrated that the expression of mRNA transcripts for BMPR2 and Id1 in PAEC was reduced after exposure to 24 hours’ hypoxia. In addition, E2 decreased the expression of phosphorylated Smad (p-Smad)1/5/8 in a dose-dependent manner (10 −10 M-10 −7 M) and p-Smad1/5/8 expression were decreased about 80% by 10 −7 M of E2. These attenuation of p-Smad1/5/8 expression were rescued by ICI182.780. Third, under normoxic condition with cobalt chloride or deferoxamine to prevent the degradation of HIF (hypoxia-inducible factor)-1α, the presence of E2 decreased the expression of p-Smad1/5/8 like under hypoxia. Conversely, administration of HIF-1α inhibitor (YC-1) canceled the reduced expression of p-Smad1/5/8 like under normoxia. Under hypoxia, the presence of E2 attenuates the BMPR signal pathway in PAEC in vitro. Our data indicated that the advance effect of E2 on BMPR signal pathway was associated with HIF-1α and estrogen receptor. Our observations provide the first evidence that female sex hormone affects on BMPR signal pathway, which can offer new strategies for the treatment of PAH.

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Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growth

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.12.109 ◽

2007 ◽

Vol 353 (3) ◽

pp. 817-822 ◽

Cited By ~ 36

Author(s):

Roberto Montesano

Keyword(s):

Epithelial Cells ◽

Bone Morphogenetic Protein ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Bone Morphogenetic Protein 4 ◽

Invasive Growth ◽

Lumen Formation ◽

Morphogenetic Protein

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Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2008.07.007 ◽

2008 ◽

Vol 374 (1) ◽

pp. 164-168 ◽

Cited By ~ 27

Author(s):

Roberto Montesano ◽

Rita Sarközi ◽

Herbert Schramek

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Bone Morphogenetic Protein ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Bone Morphogenetic Protein 4 ◽

Morphogenetic Protein

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ΔNp63α-Mediated Activation of Bone Morphogenetic Protein Signaling Governs Stem Cell Activity and Plasticity in Normal and Malignant Mammary Epithelial Cells

Cancer Research ◽

10.1158/0008-5472.can-12-2862 ◽

2012 ◽

Vol 73 (2) ◽

pp. 1020-1030 ◽

Cited By ~ 42

Author(s):

Amanda L. Balboni ◽

Justine A. Hutchinson ◽

Andrew J. DeCastro ◽

Pratima Cherukuri ◽

Karen Liby ◽

...

Keyword(s):

Stem Cell ◽

Epithelial Cells ◽

Bone Morphogenetic Protein ◽

Mammary Epithelial Cells ◽

Cell Activity ◽

Mammary Epithelial ◽

Protein Signaling ◽

Bone Morphogenetic Protein Signaling ◽

Morphogenetic Protein ◽

Stem Cell Activity

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Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function

Blood ◽

10.1182/blood-2010-05-285973 ◽

2011 ◽

Vol 117 (1) ◽

pp. 333-341 ◽

Cited By ~ 81

Author(s):

Victoria J. Burton ◽

Loredana I. Ciuclan ◽

Alan M. Holmes ◽

David M. Rodman ◽

Christoph Walker ◽

...

Keyword(s):

Pulmonary Artery ◽

Bone Morphogenetic Protein ◽

Barrier Function ◽

Transforming Growth Factor ◽

Pulmonary Vasculature ◽

Bone Morphogenetic Protein Receptor ◽

Protein Receptor ◽

Morphogenetic Protein

Abstract Mutations in bone morphogenetic protein receptor II (BMPR-II) underlie most heritable cases of pulmonary arterial hypertension (PAH). However, less than half the individuals who harbor mutations develop the disease. Interestingly, heterozygous null BMPR-II mice fail to develop PAH unless an additional inflammatory insult is applied, suggesting that BMPR-II plays a fundamental role in dampening inflammatory signals in the pulmonary vasculature. Using static- and flow-based in vitro systems, we demonstrate that BMPR-II maintains the barrier function of the pulmonary artery endothelial monolayer suppressing leukocyte transmigration. Similar findings were also observed in vivo using a murine model with loss of endothelial BMPR-II expression. In vitro, the enhanced transmigration of leukocytes after tumor necrosis factor α or transforming growth factor β1 stimulation was CXCR2 dependent. Our data define how loss of BMPR-II in the endothelial layer of the pulmonary vasculature could lead to a heightened susceptibility to inflammation by promoting the extravasation of leukocytes into the pulmonary artery wall. We speculate that this may be a key mechanism involved in the initiation of the disease in heritable PAH that results from defects in BMPR-II expression.

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