scholarly journals Suppressed Prostate Epithelial Development with Impaired Branching Morphogenesis in Mice Lacking Stromal Fibromuscular Androgen Receptor

2012 ◽  
Vol 26 (1) ◽  
pp. 52-66 ◽  
Author(s):  
Kuo-Pao Lai ◽  
Shinichi Yamashita ◽  
Spencer Vitkus ◽  
Chih-Rong Shyr ◽  
Shuyuan Yeh ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Growth Factor ◽  
Branching Morphogenesis ◽  
Placental Growth Factor ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Stromal Fibroblasts ◽  
Epithelial Development ◽  
Anterior Prostate ◽  
Prostate Epithelium

Abstract Using the cre-loxP system, we generated a new mouse model [double stromal androgen receptor knockout (dARKO)] with selectively deleted androgen receptor (AR) in both stromal fibroblasts and smooth muscle cells, and found the size of the anterior prostate (AP) lobes was significantly reduced as compared with those from wild-type littermate controls. The reduction in prostate size of the dARKO mouse was accompanied by impaired branching morphogenesis and partial loss of the infolding glandular structure. Further dissection found decreased proliferation and increased apoptosis of the prostate epithelium in the dARKO mouse AP. These phenotype changes were further confirmed with newly established immortalized prostate stromal cells (PrSC) from wild-type and dARKO mice. Mechanistically, IGF-1, placental growth factor, and secreted phosphoprotein-1 controlled by stromal AR were differentially expressed in PrSC-wt and PrSC-ARKO. Moreover, the conditioned media (CM) from PrSC-wt promoted prostate epithelium growth significantly as compared with CM from PrSC-dARKO. Finally, adding IGF-1/placental growth factor recombinant proteins into PrSC-dARKO CM was able to partially rescue epithelium growth. Together, our data concluded that stromal fibromuscular AR could modulate epithelium growth and maintain cellular homeostasis through identified growth factors.

scholarly journals Adverse Adipose Phenotype and Hyperinsulinemia in Gravid Mice Deficient in Placental Growth Factor

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2176-2183 ◽  
Author(s):  
Bianca Hemmeryckx ◽  
Rita van Bree ◽  
Berthe Van Hoef ◽  
Lisbeth Vercruysse ◽  
H. Roger Lijnen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Adrenergic Receptors ◽  
Growth Factor Receptor ◽  
Placental Growth Factor ◽  
Peroxisome Proliferator ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adipocyte Hypertrophy ◽  
Endothelial Growth Factor

Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF−/−) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF−/− pregnancies. PlGF−/− mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1 was decreased accordingly. Moreover, PlGF−/− mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF−/− and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-γ2) and thermogenesis (β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF−/− mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.

A critical role of placental growth factor in the induction of inflammation and edema formation

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 560-567 ◽  
Author(s):  
Hajimu Oura ◽  
Jennifer Bertoncini ◽  
Paula Velasco ◽  
Lawrence F. Brown ◽  
Peter Carmeliet ◽  
...  
Keyword(s):  
Growth Factor ◽  
Inflammatory Response ◽  
Critical Role ◽  
Placental Growth Factor ◽  
Delayed Type Hypersensitivity ◽  
Epidermal Keratinocytes ◽  
Wild Type ◽  
Edema Formation ◽  
Cutaneous Inflammation ◽  
Endothelial Growth Factor

Angiogenesis is a prominent feature of a number of inflammatory human diseases, including rheumatoid arthritis, psoriasis, and cutaneous delayed-type hypersensitivity (DTH) reactions. Up-regulation of placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, has been found in several conditions associated with pathologic angiogenesis; however, its distinct role in the control of angiogenesis has remained unclear. To directly investigate the biologic function of PlGF in cutaneous inflammation and angiogenesis, DTH reactions were investigated in the ear skin of wild-type mice, of PlGF-deficient mice, and of transgenic mice with targeted overexpression of human PlGF-2 in epidermal keratinocytes, driven by a keratin 14 promoter expression construct. Chronic transgenic delivery of PlGF-2 to murine epidermis resulted in a significantly increased inflammatory response, associated with more pronounced vascular enlargement, edema, and inflammatory cell infiltration than seen in wild-type mice. Conversely, PlGF deficiency resulted in a diminished and abbreviated inflammatory response, together with a reduction of inflammatory angiogenesis and edema formation. VEGF expression was up-regulated at a comparable level in the inflamed skin of all genotypes. These findings reveal that placental growth factor plays a critical role in the control of cutaneous inflammation, and they suggest inhibition of PlGF bioactivity as a potential new approach for anti-inflammatory therapy.

scholarly journals Altered Differentiation and Proliferation of Prostate Epithelium in Mice Lacking the Androgen Receptor Cofactor p44/WDR77

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3941-3953 ◽  
Author(s):  
Shen Gao ◽  
Hong Wu ◽  
Fen Wang ◽  
Zhengxin Wang
Keyword(s):  
Androgen Receptor ◽  
Growth And Development ◽  
Target Gene ◽  
Secretory Proteins ◽  
Wild Type ◽  
Altered Expression ◽  
Prostate Development ◽  
Differentiation And Proliferation ◽  
Prostate Epithelium ◽  
Prostate Growth

Although it has been observed that various cofactors modulate activity of the androgen receptor (AR), the specific relationship between AR cofactors and prostate development and functions has not been well studied. To determine whether AR cofactor p44/WDR77 is important in prostate growth and development, we examined prostate architecture in p44/WDR77-null mice and wild-type (WT) littermates. Prostate glands from p44/WDR77-deficient animals were not only smaller than those from WT mice but also had fewer branches and terminal duct tips and were deficient in production of secretory proteins. The p44/WDR77-null prostate tissue was less differentiated and hyperproliferative relative to WT littermates. In addition, the altered expression of androgen-regulated genes was observed in the p44/WDR77-null prostate. Thus, these results suggest that the AR cofactor p44/WDR77 plays important roles in prostate growth and differentiation by modulating AR-target gene expression.

Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development

Development ◽  
1999 ◽  
Vol 126 (2) ◽  
pp. 335-344 ◽  
Author(s):  
J.F. Wiesen ◽  
P. Young ◽  
Z. Werb ◽  
G.R. Cunha
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Branching Morphogenesis ◽  
Renal Capsule ◽  
Wild Type ◽  
Ductal Morphogenesis ◽  
Alveolar Development ◽  
Stromal Component ◽  
Epidermal Growth

Stromal-epithelial interactions are critical in determining patterns of growth, development and ductal morphogenesis in the mammary gland, and their perturbations are significant components of tumorigenesis. Growth factors such as epidermal growth factor (EGF) contribute to these reciprocal stromal-epithelial interactions. To determine the role of signaling through the EGF receptor (EGFR) in mammary ductal growth and branching, we used mice with a targeted null mutation in the Egfr. Because Egfr−/− mice die perinatally, transplantation methods were used to study these processes. When we transplanted neonatal mammary glands under the renal capsule of immuno-compromised female mice, we found that EGFR is essential for mammary ductal growth and branching morphogenesis, but not for mammary lobulo-alveolar development. Ductal growth and development was normal in transplants of mammary epithelium from Egfr−/− mice into wild-type (WT) gland-free fat pads and in tissue recombinants prepared with WT stroma, irrespective of the source of epithelium (StromaWT/Epi−/−, StromaWT/EpiWT). However, ductal growth and branching was impaired in tissue recombinants prepared with Egfr−/− stroma (Stroma−/−/EpiWT, Stroma−/−/Epi−/−). Thus, for ductal morphogenesis, signaling through the EGFR is required only in the stromal component, the mammary fat pad. These data indicate that the EGFR pathway plays a key role in the stromal-epithelial interactions required for mammary ductal growth and branching morphogenesis. In contrast, signaling through the EGFR is not essential for lobulo-alveolar development. Stimulation of lobulo-alveolar development in the mammary gland grafts by inclusion of a pituitary isograft under the renal capsule as a source of prolactin resulted in normal alveolar development in both Egfr−/− and wild-type transplants. Through the use of tissue recombinants and transplantation, we have gained new insights into the nature of stromal-epithelial interactions in the mammary gland, and how they regulate ductal growth and branching morphogenesis.

scholarly journals Disruption of Prostate Epithelial Androgen Receptor Impedes Prostate Lobe-Specific Growth and Function

Endocrinology ◽  
2007 ◽  
Vol 148 (5) ◽  
pp. 2264-2272 ◽  
Author(s):  
Ulla Simanainen ◽  
Charles M. Allan ◽  
Patrick Lim ◽  
Stephen McPherson ◽  
Mark Jimenez ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Functional Differentiation ◽  
Branching Morphogenesis ◽  
Testis Weight ◽  
Structural Differentiation ◽  
Prostate Development ◽  
Prostate Epithelium

Prostate development and maturation requires stromal-epithelial interactions and androgen action via the androgen receptor (AR) within these compartments. However, the specific roles of epithelial and stromal AR in postnatal prostate differentiation are unclear. We used Cre-LoxP technology to determine the prostate phenotype in mice with epithelial-selective genetic inactivation of the AR leaving the stromal AR functionally intact. We find that prostate development abolished in mice globally lacking a functional AR can be rescued by restricting the AR knockout to the postnatal prostate epithelium. We show that, at 8 wk of age, prostate epithelial AR knockout (PEARKO) mice exhibit prostate development with normal branching morphogenesis but lobe-specific decrease in prostate weight and hindered structural and functional differentiation of the mature prostate epithelium. No change was observed in PEARKO testis weight or serum testosterone compared with littermate controls. The most striking change was increased proliferation and abnormal lesions of epithelial cells predominantly in the anterior lobe of PEARKO mice. These findings highlight the vital role of stromal AR in postnatal prostate growth and structural differentiation and emphasize the requirement of epithelial AR in maintaining functional differentiation and restraining proliferation of epithelial cells in a lobe-specific manner. This unique PEARKO mouse provides a new paradigm with which to define the molecular mechanisms of the androgen signaling in mature prostate lobes in vivo and provides insight into the identification of better targets for treatment of prostate cancer and hyperplasia.

scholarly journals Altered prostate epithelial development in mice lacking the androgen receptor in stromal fibroblasts

The Prostate ◽  
2011 ◽  
Vol 72 (4) ◽  
pp. 437-449 ◽  
Author(s):  
Shengqiang Yu ◽  
Chiuan-Ren Yeh ◽  
Yuanjie Niu ◽  
Hong-Chiang Chang ◽  
Yu-Chieh Tsai ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Stromal Fibroblasts ◽  
Epithelial Development

scholarly journals Corrigendum to: “Suppressed Prostate Epithelial Development with Impaired Branching Morphogenesis in Mice Lacking Stromal Fibromuscular Androgen Receptor”

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Kuo-Pao Lai ◽  
Shinichi Yamashita ◽  
Spencer Vitkus ◽  
Chih-Rong Shyr ◽  
Shuyuan Yeh ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Branching Morphogenesis ◽  
Epithelial Development

The role of placental growth factor in regulating fetal brain vascular development

2014 ◽  
Author(s):  
Matthew T Ratsep ◽  
Bruno Zavan ◽  
Nicki Peterson ◽  
Leandra Tolusso ◽  
Vanessa Kay ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Development ◽  
Fetal Brain ◽  
Placental Growth Factor
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