Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms

Verónica Torres-Estay, Daniela V. Carreño, Patricia Fuenzalida, Anica Watts, Ignacio F. San Francisco, Viviana P. Montecinos, Paula C. Sotomayor, John Ebos, Gary J. Smith, Alejandro S. Godoy

Resultado de la investigación: Research - revisión exhaustivaArticle

Resumen

Background: Sex-related differences in the role of androgen have been reported in cardiovascular diseases and angiogenesis. Moreover, androgen receptor (AR) has been causally involved in the homeostasis of human prostate endothelial cells. However, levels of expression, functionality and biological role of AR in male- and female-derived human endothelial cells (ECs) remain poorly characterized. The objectives of this work were (1) to characterize the functional expression of AR in male- and female-derived human umbilical vein endothelial cell (HUVEC), and (2) to specifically analyze the biological effects of DHT, and the role of AR on these effects, in male-derived HUVECs (mHUVECs). Results: Immunohistochemical analyses of tissue microarrays from benign human tissues confirmed expression of AR in ECs from several androgen-regulated and non-androgen-regulated human organs. Functional expression of AR was validated in vitro in male- and female-derived HUVECs using quantitative RT-PCR, immunoblotting and AR-mediated transcriptional activity assays. Our results indicated that functional expression of AR in male- and female-derived HUVECs was heterogeneous, but not sex dependent. In parallel, we analyzed in depth the biological effects of DHT, and the role of AR on these effects, on proliferation, survival and tube formation capacity in mHUVECs. Our results indicated that DHT did not affect mHUVEC survival; however, DHT stimulated mHUVEC proliferation and suppressed mHUVEC tube formation capacity. While the effect of DHT on proliferation was mediated through AR, the effect of DHT on tube formation did not depend on the presence of a functional AR, but rather depended on the ability of mHUVECs to further metabolize DHT. Conclusions: (1) Heterogeneous expression of AR in male- and female-derived HUVEC could define the presence of functionally different subpopulations of ECs that may be affected differentially by androgens, which could explain, at least in part, the pleiotropic effects of androgen on vascular biology, and (2) DHT, and metabolites of DHT, generally thought to represent progressively more hydrophilic products along the path to elimination, may have differential roles in modulating the biology of human ECs through AR-dependent and AR-independent mechanisms, respectively.

IdiomaEnglish
Páginas25-38
Número de páginas14
PublicaciónAngiogenesis
Volumen20
Número de edición1
DOI
EstadoPublished - 1 feb 2017

Huella dactilar

Androgen Receptors
Androgens
Homeostasis
Endothelial Cells
Endothelial cells
Human Umbilical Vein Endothelial Cells
Survival
Tissue
Tissue Array Analysis
Immunoblotting
Sex Characteristics
Blood Vessels
Prostate
Cardiovascular Diseases
Polymerase Chain Reaction
In Vitro Techniques
Microarrays
Metabolites
Assays

Keywords

    ASJC Scopus subject areas

    • Physiology
    • Clinical Biochemistry
    • Cancer Research

    Citar esto

    Torres-Estay, V., Carreño, D. V., Fuenzalida, P., Watts, A., San Francisco, I. F., Montecinos, V. P., ... Godoy, A. S. (2017). Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms. Angiogenesis, 20(1), 25-38. DOI: 10.1007/s10456-016-9525-6
    Torres-Estay, Verónica ; Carreño, Daniela V. ; Fuenzalida, Patricia ; Watts, Anica ; San Francisco, Ignacio F. ; Montecinos, Viviana P. ; Sotomayor, Paula C. ; Ebos, John ; Smith, Gary J. ; Godoy, Alejandro S./ Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms. En: Angiogenesis. 2017 ; Vol. 20, N.º 1. pp. 25-38
    @article{73a6679bd184474a9a1f84ae88a31d99,
    title = "Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms",
    abstract = "Background: Sex-related differences in the role of androgen have been reported in cardiovascular diseases and angiogenesis. Moreover, androgen receptor (AR) has been causally involved in the homeostasis of human prostate endothelial cells. However, levels of expression, functionality and biological role of AR in male- and female-derived human endothelial cells (ECs) remain poorly characterized. The objectives of this work were (1) to characterize the functional expression of AR in male- and female-derived human umbilical vein endothelial cell (HUVEC), and (2) to specifically analyze the biological effects of DHT, and the role of AR on these effects, in male-derived HUVECs (mHUVECs). Results: Immunohistochemical analyses of tissue microarrays from benign human tissues confirmed expression of AR in ECs from several androgen-regulated and non-androgen-regulated human organs. Functional expression of AR was validated in vitro in male- and female-derived HUVECs using quantitative RT-PCR, immunoblotting and AR-mediated transcriptional activity assays. Our results indicated that functional expression of AR in male- and female-derived HUVECs was heterogeneous, but not sex dependent. In parallel, we analyzed in depth the biological effects of DHT, and the role of AR on these effects, on proliferation, survival and tube formation capacity in mHUVECs. Our results indicated that DHT did not affect mHUVEC survival; however, DHT stimulated mHUVEC proliferation and suppressed mHUVEC tube formation capacity. While the effect of DHT on proliferation was mediated through AR, the effect of DHT on tube formation did not depend on the presence of a functional AR, but rather depended on the ability of mHUVECs to further metabolize DHT. Conclusions: (1) Heterogeneous expression of AR in male- and female-derived HUVEC could define the presence of functionally different subpopulations of ECs that may be affected differentially by androgens, which could explain, at least in part, the pleiotropic effects of androgen on vascular biology, and (2) DHT, and metabolites of DHT, generally thought to represent progressively more hydrophilic products along the path to elimination, may have differential roles in modulating the biology of human ECs through AR-dependent and AR-independent mechanisms, respectively.",
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    author = "Verónica Torres-Estay and Carreño, {Daniela V.} and Patricia Fuenzalida and Anica Watts and {San Francisco}, {Ignacio F.} and Montecinos, {Viviana P.} and Sotomayor, {Paula C.} and John Ebos and Smith, {Gary J.} and Godoy, {Alejandro S.}",
    year = "2017",
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    Torres-Estay, V, Carreño, DV, Fuenzalida, P, Watts, A, San Francisco, IF, Montecinos, VP, Sotomayor, PC, Ebos, J, Smith, GJ & Godoy, AS 2017, 'Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms' Angiogenesis, vol. 20, n.º 1, pp. 25-38. DOI: 10.1007/s10456-016-9525-6

    Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms. / Torres-Estay, Verónica; Carreño, Daniela V.; Fuenzalida, Patricia; Watts, Anica; San Francisco, Ignacio F.; Montecinos, Viviana P.; Sotomayor, Paula C.; Ebos, John; Smith, Gary J.; Godoy, Alejandro S.

    En: Angiogenesis, Vol. 20, N.º 1, 01.02.2017, p. 25-38.

    Resultado de la investigación: Research - revisión exhaustivaArticle

    TY - JOUR

    T1 - Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms

    AU - Torres-Estay,Verónica

    AU - Carreño,Daniela V.

    AU - Fuenzalida,Patricia

    AU - Watts,Anica

    AU - San Francisco,Ignacio F.

    AU - Montecinos,Viviana P.

    AU - Sotomayor,Paula C.

    AU - Ebos,John

    AU - Smith,Gary J.

    AU - Godoy,Alejandro S.

    PY - 2017/2/1

    Y1 - 2017/2/1

    N2 - Background: Sex-related differences in the role of androgen have been reported in cardiovascular diseases and angiogenesis. Moreover, androgen receptor (AR) has been causally involved in the homeostasis of human prostate endothelial cells. However, levels of expression, functionality and biological role of AR in male- and female-derived human endothelial cells (ECs) remain poorly characterized. The objectives of this work were (1) to characterize the functional expression of AR in male- and female-derived human umbilical vein endothelial cell (HUVEC), and (2) to specifically analyze the biological effects of DHT, and the role of AR on these effects, in male-derived HUVECs (mHUVECs). Results: Immunohistochemical analyses of tissue microarrays from benign human tissues confirmed expression of AR in ECs from several androgen-regulated and non-androgen-regulated human organs. Functional expression of AR was validated in vitro in male- and female-derived HUVECs using quantitative RT-PCR, immunoblotting and AR-mediated transcriptional activity assays. Our results indicated that functional expression of AR in male- and female-derived HUVECs was heterogeneous, but not sex dependent. In parallel, we analyzed in depth the biological effects of DHT, and the role of AR on these effects, on proliferation, survival and tube formation capacity in mHUVECs. Our results indicated that DHT did not affect mHUVEC survival; however, DHT stimulated mHUVEC proliferation and suppressed mHUVEC tube formation capacity. While the effect of DHT on proliferation was mediated through AR, the effect of DHT on tube formation did not depend on the presence of a functional AR, but rather depended on the ability of mHUVECs to further metabolize DHT. Conclusions: (1) Heterogeneous expression of AR in male- and female-derived HUVEC could define the presence of functionally different subpopulations of ECs that may be affected differentially by androgens, which could explain, at least in part, the pleiotropic effects of androgen on vascular biology, and (2) DHT, and metabolites of DHT, generally thought to represent progressively more hydrophilic products along the path to elimination, may have differential roles in modulating the biology of human ECs through AR-dependent and AR-independent mechanisms, respectively.

    AB - Background: Sex-related differences in the role of androgen have been reported in cardiovascular diseases and angiogenesis. Moreover, androgen receptor (AR) has been causally involved in the homeostasis of human prostate endothelial cells. However, levels of expression, functionality and biological role of AR in male- and female-derived human endothelial cells (ECs) remain poorly characterized. The objectives of this work were (1) to characterize the functional expression of AR in male- and female-derived human umbilical vein endothelial cell (HUVEC), and (2) to specifically analyze the biological effects of DHT, and the role of AR on these effects, in male-derived HUVECs (mHUVECs). Results: Immunohistochemical analyses of tissue microarrays from benign human tissues confirmed expression of AR in ECs from several androgen-regulated and non-androgen-regulated human organs. Functional expression of AR was validated in vitro in male- and female-derived HUVECs using quantitative RT-PCR, immunoblotting and AR-mediated transcriptional activity assays. Our results indicated that functional expression of AR in male- and female-derived HUVECs was heterogeneous, but not sex dependent. In parallel, we analyzed in depth the biological effects of DHT, and the role of AR on these effects, on proliferation, survival and tube formation capacity in mHUVECs. Our results indicated that DHT did not affect mHUVEC survival; however, DHT stimulated mHUVEC proliferation and suppressed mHUVEC tube formation capacity. While the effect of DHT on proliferation was mediated through AR, the effect of DHT on tube formation did not depend on the presence of a functional AR, but rather depended on the ability of mHUVECs to further metabolize DHT. Conclusions: (1) Heterogeneous expression of AR in male- and female-derived HUVEC could define the presence of functionally different subpopulations of ECs that may be affected differentially by androgens, which could explain, at least in part, the pleiotropic effects of androgen on vascular biology, and (2) DHT, and metabolites of DHT, generally thought to represent progressively more hydrophilic products along the path to elimination, may have differential roles in modulating the biology of human ECs through AR-dependent and AR-independent mechanisms, respectively.

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    KW - Androgens

    KW - Angiogenesis

    KW - Endothelial cells

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    Torres-Estay V, Carreño DV, Fuenzalida P, Watts A, San Francisco IF, Montecinos VP y otros. Androgens modulate male-derived endothelial cell homeostasis using androgen receptor-dependent and receptor-independent mechanisms. Angiogenesis. 2017 feb 1;20(1):25-38. Disponible desde, DOI: 10.1007/s10456-016-9525-6