Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D3 production

1990 ◽  
Vol 258 (5) ◽  
pp. E780-E789 ◽  
Author(s):  
R. Vieth ◽  
K. McCarten ◽  
K. H. Norwich
Keyword(s):  
Specific Activity ◽  
Metabolic Clearance ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Dose Dependent

To understand the relationships among 1) the dose of 25-hydroxyvitamin D [25(OH)D] in vivo, 2) the activity of 1-hydroxylase in renal mitochondria, and 3) the production of 1,25-dihydroxyvitamin D [1,25(OH)2D] in vivo, we gave rats different chronic or acute doses of 25-hydroxyvitamin D3 [25(OH)D3]. We followed the metabolism of intracardially administered [25-hydroxy-26,27-methyl-3H]cholecalciferol [25(OH)[3H]D3] for 24 h before killing by measuring extracts of serum by chromatography. Specific activity of 1-hydroxylase in kidney was measured at death. In rats given 0-2,000 pmol 25(OH)D3 chronically by mouth, there was a dose-dependent decline in the percent of serum radioactivity made up of 1,25-dihydroxy-[26,27-methyl-3H]cholecalciferol [1,25(OH)2[3H]D3] as well as a decline in mitochondrial 1-hydroxylase, and these correlated significantly (r = 0.83, P less than 0.001). Serum %1,25(OH)2[3H]D3 in this experiment ranged from 0.8 to 42%. A small part of this range could be accounted for by a faster metabolic clearance rate (MCR) of 1,25(OH)2D3 from rats supplemented with 25(OH)D3 (MCR, 2.12 +/- 0.10 ml/min) compared with rats restricted in vitamin D (MCR, 0.94 +/- 0.06 ml/min, P less than 0.001). The activity of 1-hydroxylase was by far the major factor determining serum %1,25(OH)2[3H]D3. When different acute doses of 25(OH)D3 were given to rats with identical specific activities of 1-hydroxylase, the resulting 1,25(OH)2D3 concentrations in serum correlated with the 25(OH)D3 dose (r = 0.99, P less than 0.001). We conclude that the behavior of 1-hydroxylase in vivo is analogous to the classic behavior in vitro of an enzyme functioning below its Michaelis constant (Km). The amount of 1-hydroxylase present in renal mitochondria determines the fraction (not simply the quantity) of 25(OH)D metabolized to 1,25(OH)2D3 in vivo.

Metabolism of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 and its sensitivity to ketoconazole in 1α,25-dihydroxyvitamin D3-differentiated HL60 cells

1989 ◽  
Vol 3 (3) ◽  
pp. 199-205 ◽  
Author(s):  
M. E. Hayes ◽  
D. Bayley ◽  
E. B. Mawer
Keyword(s):  
High Performance ◽  
Cell Number ◽  
Dependent Manner ◽  
Macrophage Phenotype ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Dose Dependent

ABSTRACT Regulation of the metabolism of [3H]25-hydroxyvitamin D3 ([3H]25-(OH)D3) in vitro to material with the characteristics of [3H]24,25-dihydroxyvitamin D3 ([3H]24,25-(OH)2D3) has been studied in the human promyelocytic cell line HL60. Synthesis of 24,25-(OH)2D3 was induced in a dose-dependent manner in cells pretreated with 0·1–100 nm 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) for 4 days. This treatment also inhibited cell proliferation and stimulated differentiation to a macrophage phenotype that was characterized by staining for non-specific esterase (NSE) activity. The ability to synthesize [3H]24,25-(OH)2D3 from [3H]25-(OH)D3 and the expression of NSE activity both responded to changes in concentration of 1α,25-(OH)2D3 in the culture medium in a parallel manner. Synthesis of [3H]24,25-(OH)2D3 was linear when the incubation time was between 1 and 8 h and the cell number between 1 and 12×106 cells/incubation. The optimum substrate concentration for its synthesis was 125 nm, giving an apparent Michaelis constant of 360 nm. The identity of the [3H]24,25-(OH)2D3 synthesized by these cells was confirmed by co-chromatography with authentic 24,25-(OH)2D3 on normal-phase and reverse-phase high-performance liquid chromatography systems and by its reaction to sodium-m-periodate. Cells that had been exposed to 100 nm 1α,25-(OH)2D3 for 4 days synthesized 2·17±0·07 (s.e.m.) pmol 24,25-(OH)2D3/106 cells per h. This synthesis was inhibited in a dose-dependent manner over a concentration range of 0·01–1 μm by the drug ketoconazole, an antimycotic imidazole which is a known inhibitor of certain cytochrome P-450 enzyme systems, suggesting that the HL60 25-(OH)D3-24-hydroxylase is also a P-450-dependent enzyme system.

Effect of 1,25-dihydroxyvitamin D3 on rat pituitary prolactin release

1987 ◽  
Vol 116 (4) ◽  
pp. 459-464 ◽  
Author(s):  
Kid Törnquist
Keyword(s):  
Pituitary Cells ◽  
Dihydroxyvitamin D3 ◽  
Enhancing Effect ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Rat Pituitary ◽  
25 Hydroxyvitamin D ◽  
Pituitary Prolactin

Abstract. The effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on PRL secretion from rat pituitary in vivo and in vitro was investigated. Treating the rats for three days with 0.05 μg/kg per day had no effect on basal PRL secretion, whereas the TRH-induced PRL secretion was increased (P < 0.001). The enhancing effect of 1,25(OH)2D3 was blunted by verapamil. Incubating dispersed anterior pituitary cells with 10−8 mol/l 1,25(OH)2D3 induced a significant increase in PRL secretion after 96 h (364 ± 30 ng/well vs 481 ± 33 ng/well, P < 0.001; mean ± sem) compared with control cells. The TRH-induced PRL secretion was increased in cells incubated with 1,25(OH)2D3 for 144 h (0.766 ± 0.061 vs 1.024 ± 0.076 μg/well, P < 0.05; mean ± sem) compared with control cells. Neither 25-hydroxyvitamin D3 (25OH-D3) nor 24,25-dihydroxyvitamin D3 had any effects on the PRL secretion. However, when the cells were incubated with both 10−8 mol/l 1,25(OH)2D3 and 10−6 mol/l 25OHD3, the enhancing effect of 1,25(OH)2D3 on the basal PRL secretion was blunted. The results suggest that 1,25(OH)2D3 possibly affects the regulation of PRL release from the rat pituitary and that this effect is specific for 1,25(OH)2D3.

Vitamin D kinetics in vivo: effect of 1,25-dihydroxyvitamin D administration

1989 ◽  
Vol 256 (5) ◽  
pp. E686-E691
Author(s):  
B. P. Halloran ◽  
M. E. Castro
Keyword(s):  
Serum Concentration ◽  
Chronic Administration ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
25 Hydroxyvitamin D ◽  
Kinetics In Vivo

Administration of 1,25-dihydroxyvitamin D [1,25(OH)2D] can increase the metabolic clearance rate (MCR) of 25-hydroxyvitamin D [25(OH)D]. To determine whether administration of 1,25(OH)2D can also influence the metabolic clearance rates (MCR) of 1,25(OH)2D and 24,25-dihydroxyvitamin D 24,25(OH)2D, we measured metabolic clearance of 1,25(OH)2D, 24,25(OH)2D, and 25(OH)D in rats in which the serum concentration of 1,25(OH)2D was increased by continuous infusion. Infusion of 1,25(OH)2D (12 days at 75 pmol/day) increased serum 1,25(OH)2D from 128 +/- 11 to 244 +/- 14 pg/ml (P less than 0.005) and increased MCR from 169 +/- 13 to 210 +/- 9 microliters.min-1.kg-1 or 24% (P less than 0.025). Increasing serum 1,25(OH)2D to 330-360 pg/ml increased MCR 72%. Infusion of 1,25(OH)2D decreased serum 24,25(OH)2D from 3.5 +/- 0.5 to 2.4 +/- 0.3 ng/ml (P less than 0.05), increased MCR from 25 +/- 2 to 48 +/- 6 microliters.min-1.kg-1 (P less than 0.0025), and increased the production rate (PR) from 70 +/- 11 to 124 +/- 26 pg.min-1.kg-1 (P less than 0.05). Infusion of 1,25(OH)2D decreased serum 25(OH)D from 13.0 +/- 0.5 to 8.0 +/- 0.5 ng/ml (P less than 0.005) and increased MCR from 45 +/- 1 to 75 +/- 7 microliters.min-1.kg-1 (P less than 0.001) but had no effect on PR. The data indicate that increasing serum 1,25(OH)2D by chronic administration can increase the MCR of 1,25(OH)2D and suggest that 1,25(OH)2D can feedback regulate its serum concentration by regulating its MCR. The data also suggest that 1,25(OH)2D administration can increase the MCRs of 24,25(OH)2D and 25(OH)D.

Metabolism of 25-hydroxyvitamin D3 in rats: low-calcium diet vs. calcitriol infusion

1992 ◽  
Vol 262 (3) ◽  
pp. E359-E367 ◽  
Author(s):  
M. J. Bolt ◽  
W. E. Jensen ◽  
M. D. Sitrin
Keyword(s):  
Side Chain ◽  
Metabolic Clearance ◽  
Chain Oxidation ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Low Calcium Diet ◽  
Subsequent Degradation ◽  
Dramatic Rise ◽  
25 Hydroxyvitamin D

It has been proposed that the decreased serum level of 25-hydroxyvitamin D [25(OH)D] observed with dietary Ca restriction is mediated by an increase in circulating 1,25-dihydroxyvitamin D [1,25(OH)2D]. We compared the effects of endogenous and exogenous elevations in serum 1,25(OH)2D on the production rate (PR), metabolic clearance rate (MCR), and excretory pathways of [3H]25(OH)D3 in rats, with the use of steady-state techniques. Low-Ca diet and 1,25(OH)2D3 infusion caused comparable reductions in serum 25(OH)D and elevations in 1,25(OH)2D. Low-Ca diet lowered serum 25(OH)D by increasing MCR from 21.8 +/- 3.2 to 29.1 +/- 5.4 (SD) microliters.min-1.kg-1 (P less than or equal to 0.005) and decreasing PR from 944 +/- 161 to 663 +/- 163 pg.Ain-1.kg-1 (P less than or equal to 0.001). In contrast, 1,25(OH)2D3 infusion produced a dramatic rise in the MCR of 25(OH)D from 23.4 +/- 4.5 to 62.8 +/- 13.7 microliters.min-1.kg-1 (P less than or equal to 0.001) and also increased the PR from 943 +/- 165 to 1,500 +/- 337 pg.min-1.kg-1 (P less than or equal to 0.001). With 1,25(OH)2D3 infusion, urinary excretion of metabolites of [3H]25(OH)D3 rose rapidly, and kidney homogenates from these rats demonstrated vigorous side-chain oxidation of [3H]25(OH)D3. With low-Ca diet, urinary tritium excretion increased more gradually, and no direct side-chain oxidation of [3H]25(OH)D3 occurred in vitro. The increased MCR of 25(OH)D3 with low-Ca diet could be accounted for by enhanced synthesis of 1,25(OH)2D3 and subsequent degradation in target tissues.

1,25-Dihydroxyvitamin D3 downregulates the rat intestinal vitamin D3-25-hydroxylaseCYP27A

2001 ◽  
Vol 281 (2) ◽  
pp. E315-E325 ◽  
Author(s):  
Catherine Theodoropoulos ◽  
Christian Demers ◽  
Ali Mirshahi ◽  
Marielle Gascon-Barré
Keyword(s):  
Vitamin D ◽  
Direct Action ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Protein Levels ◽  
25 Hydroxyvitamin D ◽  
Extrahepatic Tissues ◽  
Mrna Half Life

The vitamin D3-25-hydroxylase CYP27A is located predominantly in liver, but its expression is also detected in extrahepatic tissues. Our aim was to evaluate the regulation of CYP27A by vitamin D3 (D3) or its metabolites in rat duodena. Vitamin D-depleted rats were repleted with D3, 25-hydroxyvitamin D (25OHD), or 1,25-dihydroxyvitamin D3[1,25(OH)2D3] or acutely injected 1,25(OH)2D3 to investigate the mechanisms of action of the hormone. All D3 compounds led to a progressive decrease in CYP27A mRNA, with levels after D3 representing 20% of that observed in D depletion. 25OHD decreased CYP27A mRNA by 55%, whereas 1,25(OH)2D3 led to a 40% decrease, which was accompanied by a 31% decrease in CYP27A protein levels and an 89% decrease in enzyme activity. Peak circulating 1,25(OH)2D3 concentrations were, however, the highest in D3-repleted, followed by 25OHD- and 1,25(OH)2D3-repleted animals. 1,25(OH)2D3 resulted in a decrease in both CYP27A mRNA half-life and transcription rate. Our data illustrate that the intestine expresses the D3-25-hydroxylase and that the gene is highly regulated in vivo through a direct action of 1,25(OH)2D3 or through the local production of D3 metabolites.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

Increased Circulatory Extrarenal 1α,25-Dihydroxyvitamin D3 in Bilaterally Nephrectomized Rats

2020 ◽  
Vol 20 (9) ◽  
pp. 1523-1530
Author(s):  
Murat Dabak ◽  
Durrin O. Dabak ◽  
Tuncay Kuloglu ◽  
Ersoy Baydar ◽  
Hakan Bulut ◽  
...  
Keyword(s):  
Immune Cells ◽  
Low Dose ◽  
Systemic Circulation ◽  
Bilateral Nephrectomy ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
Inflammatory Conditions ◽  
Calcium Phosphorus ◽  
25 Hydroxyvitamin D

Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown. Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS). Methods: Renal 1,25-D synthesis was terminated through bilateral nephrectomy in rats. The rats received intraperitoneal LPS (50 μg/kg BW) three times and the experiment was ended 24 hours after nephrectomy. Serum 1,25-D, 25-D, calcium, phosphorus, intact parathyroid hormone, and calcitonin levels were measured and immunohistochemistry was applied to detect the sources of extrarenal 1,25- D synthesis. Results: Circulatory 1,25-D concentration remarkably increased in both LPS-treated and non-treated bilaterally nephrectomized rats. Elevated circulatory 1,25-D did not have hypercalcemic endocrinal effects. The increased 1,25-D level also resulted in a concurrent rapid and dramatic depletion of circulatory 25-D. Conclusions: Extrarenal 1,25-D could enter into the systemic circulation and, therefore, might have systemic effects besides its autocrine and paracrine functions.

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

Safflower Yellow Prevents Pulmonary Metastasis of Breast Cancer by Inhibiting Tumor Cell Invadopodia

2016 ◽  
Vol 44 (07) ◽  
pp. 1491-1506 ◽  
Author(s):  
Huiying Fu ◽  
Renjie Wu ◽  
Yuanyuan Li ◽  
Lizong Zhang ◽  
Xiaofang Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Pulmonary Metastasis ◽  
Breast Cancer Cells ◽  
Dependent Cell ◽  
Response Profiles ◽  
Dose Dependent

Carthamus tinctorius L. is a traditional Chinese medicine that activates blood circulation and dissipates blood stasis, and has been extensively used as antitumor treatment in a clinical setting in single or in compound preparation form. However, empirical evidence and a better understanding of the possible mechanisms involved are still required. Here, we investigated the role of safflower yellow (SY), the active ingredient of C. tinctorius, in the pulmonary metastasis of breast cancer, and the underlying mechanism of action. EGF-meditated time- and dose-dependent cell response profiles were applied to screen for the activity of SY in vitro, while orthotopic lung metastasis and intravenous injection were used to evaluate the antimetastatic role of SY in vivo. SY could dose-dependently inhibit EGF-mediated time- and dose-dependent cell response profiles by inhibiting cytoskeletal rearrangement. We also found that SY significantly inhibited the migration of breast cancer cells in vitro and pulmonary metastasis of breast cancer cells in vivo. Consistent with these phenotypes, formation of invadopodia and the expression of MMP-9 and p-Src proteins were decreased after EGF stimulation in MBA-MD-231 cells treat with SY, as well as in lung metastatic foci. Additionally, circulating tumor cells retained in lung capillaries were also reduced. These results suggest that the antimetastatic effect of SY is due to its inhibition of invadopodia formation, which occurs mainly through Src-dependent cytoskeleton rearrangement. We suggest that SY should be considered as a potential novel therapeutic agent for the treatment of breast cancer.

scholarly journals SMAD1/5 Signaling in the Early Equine Placenta Regulates Trophoblast Differentiation and Chorionic Gonadotropin Secretion

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 3054-3064 ◽  
Author(s):  
Victoria Cabrera-Sharp ◽  
Jordan E. Read ◽  
Stephanie Richardson ◽  
Alycia A. Kowalski ◽  
Douglas F. Antczak ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Trophoblast Cells ◽  
Rt Pcr ◽  
Trophoblast Differentiation ◽  
Gonadotropin Secretion ◽  
Morphogenetic Protein ◽  
Dose Dependent

TGFβ superfamily proteins, acting via SMAD (Sma- and Mad-related protein)2/3 pathways, regulate placental function; however, the role of SMAD1/5/8 pathway in the placenta is unknown. This study investigated the functional role of bone morphogenetic protein (BMP)4 signaling through SMAD1/5 in terminal differentiation of primary chorionic gonadotropin (CG)-secreting trophoblast. Primary equine trophoblast cells or placental tissues were isolated from day 27–34 equine conceptuses. Detected by microarray, RT-PCR, and quantitative RT-PCR, equine chorionic girdle trophoblast showed increased gene expression of receptors that bind BMP4. BMP4 mRNA expression was 20- to 60-fold higher in placental tissues adjacent to the chorionic girdle compared with chorionic girdle itself, suggesting BMP4 acts primarily in a paracrine manner on the chorionic girdle. Stimulation of chorionic girdle-trophoblast cells with BMP4 resulted in a dose-dependent and developmental stage-dependent increase in total number and proportion of terminally differentiated binucleate cells. Furthermore, BMP4 treatment induced non-CG-secreting day 31 chorionic girdle trophoblast cells to secrete CG, confirming a specific functional response to BMP4 stimulation. Inhibition of SMAD2/3 signaling combined with BMP4 treatment further enhanced differentiation of trophoblast cells. Phospho-SMAD1/5, but not phospho-SMAD2, expression as determined by Western blotting was tightly regulated during chorionic girdle trophoblast differentiation in vivo, with peak expression of phospho-SMAD1/5 in vivo noted at day 31 corresponding to maximal differentiation response of trophoblast in vitro. Collectively, these experiments demonstrate the involvement of BMP4-dependent pathways in the regulation of equine trophoblast differentiation in vivo and primary trophoblast differentiation in vitro via activation of SMAD1/5 pathway, a previously unreported mechanism of TGFβ signaling in the mammalian placenta.

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