Limits...
A sex-specific role for androgens in angiogenesis.

Sieveking DP, Lim P, Chow RW, Dunn LL, Bao S, McGrath KC, Heather AK, Handelsman DJ, Celermajer DS, Ng MK - J. Exp. Med. (2010)

Bottom Line: Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs.In vivo, castration dramatically reduced neovascularization of Matrigel plugs.Androgen treatment fully reversed this effect in male mice but had no effect in female mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Heart Research Institute, Sydney 2042, Australia. sievekingd@hri.org.au

ABSTRACT
Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.

Show MeSH

Related in: MedlinePlus

DHT does not augment key angiogenic events in vitro in female ECs. (A–D) Boyden chamber (A) and scratch wounding (B) assays of migration assessed after 6 and 24 h, respectively, Matrigel assays (C), and proliferation by female ECs treated with DHT or vehicle (D; n = 4 independent experiments). P > 0.05 using ANOVA. (E) Matrigel assays of female ECs transfected with an AR overexpression plasmid and treated with DHT (n = 3 independent experiments). *, P < 0.05 using the Student’s t test. All data are expressed as means ± SEM. For each independent experiment, cells from a different donor were used.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC2822613&req=5

fig2: DHT does not augment key angiogenic events in vitro in female ECs. (A–D) Boyden chamber (A) and scratch wounding (B) assays of migration assessed after 6 and 24 h, respectively, Matrigel assays (C), and proliferation by female ECs treated with DHT or vehicle (D; n = 4 independent experiments). P > 0.05 using ANOVA. (E) Matrigel assays of female ECs transfected with an AR overexpression plasmid and treated with DHT (n = 3 independent experiments). *, P < 0.05 using the Student’s t test. All data are expressed as means ± SEM. For each independent experiment, cells from a different donor were used.

Mentions: Mounting evidence indicates that sex steroids regulate various vascular biological processes in a sex-dependent fashion (McCrohon et al., 1999; Ng et al., 2001; Ng et al., 2003b). For androgens, this is related to an approximately two- to fourfold increased AR expression in male vascular cells compared with females (McCrohon et al., 2000; Death et al., 2004). We therefore hypothesized that the proangiogenic effects of DHT observed in ECs may also be sex dependent. Unlike male ECs, exposure of female ECs to DHT had no effect on migration (Fig. 2, A and B), tubulogenesis (Fig. 2 C), or proliferation (P > 0.05; Fig. 2 D), consistent with androgen-mediated sex-specific effects. To further examine the role of the AR in mediating the sex-dependent effects of DHT on angiogenesis, we overexpressed the AR in female ECs (Fig. S2) and assessed tubulogenesis after exposure to DHT. Female ECs overexpressing the AR became responsive to DHT and displayed augmented tubulogenesis (114 ± 6% vs. 100% control value; P < 0.05 using the Student’s t test), albeit to a lesser extent than in male cells (Fig. 2 E). These findings indicate that the sex-specific effects of DHT on angiogenesis are at least in part mediated by sex differences in AR expression. As there are a variety of coregulators involved in AR signaling (Liu et al., 2003), it is also possible that many of these are also expressed in a sex-specific fashion and are important for androgenic modulation of angiogenesis.


A sex-specific role for androgens in angiogenesis.

Sieveking DP, Lim P, Chow RW, Dunn LL, Bao S, McGrath KC, Heather AK, Handelsman DJ, Celermajer DS, Ng MK - J. Exp. Med. (2010)

DHT does not augment key angiogenic events in vitro in female ECs. (A–D) Boyden chamber (A) and scratch wounding (B) assays of migration assessed after 6 and 24 h, respectively, Matrigel assays (C), and proliferation by female ECs treated with DHT or vehicle (D; n = 4 independent experiments). P > 0.05 using ANOVA. (E) Matrigel assays of female ECs transfected with an AR overexpression plasmid and treated with DHT (n = 3 independent experiments). *, P < 0.05 using the Student’s t test. All data are expressed as means ± SEM. For each independent experiment, cells from a different donor were used.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822613&req=5

fig2: DHT does not augment key angiogenic events in vitro in female ECs. (A–D) Boyden chamber (A) and scratch wounding (B) assays of migration assessed after 6 and 24 h, respectively, Matrigel assays (C), and proliferation by female ECs treated with DHT or vehicle (D; n = 4 independent experiments). P > 0.05 using ANOVA. (E) Matrigel assays of female ECs transfected with an AR overexpression plasmid and treated with DHT (n = 3 independent experiments). *, P < 0.05 using the Student’s t test. All data are expressed as means ± SEM. For each independent experiment, cells from a different donor were used.
Mentions: Mounting evidence indicates that sex steroids regulate various vascular biological processes in a sex-dependent fashion (McCrohon et al., 1999; Ng et al., 2001; Ng et al., 2003b). For androgens, this is related to an approximately two- to fourfold increased AR expression in male vascular cells compared with females (McCrohon et al., 2000; Death et al., 2004). We therefore hypothesized that the proangiogenic effects of DHT observed in ECs may also be sex dependent. Unlike male ECs, exposure of female ECs to DHT had no effect on migration (Fig. 2, A and B), tubulogenesis (Fig. 2 C), or proliferation (P > 0.05; Fig. 2 D), consistent with androgen-mediated sex-specific effects. To further examine the role of the AR in mediating the sex-dependent effects of DHT on angiogenesis, we overexpressed the AR in female ECs (Fig. S2) and assessed tubulogenesis after exposure to DHT. Female ECs overexpressing the AR became responsive to DHT and displayed augmented tubulogenesis (114 ± 6% vs. 100% control value; P < 0.05 using the Student’s t test), albeit to a lesser extent than in male cells (Fig. 2 E). These findings indicate that the sex-specific effects of DHT on angiogenesis are at least in part mediated by sex differences in AR expression. As there are a variety of coregulators involved in AR signaling (Liu et al., 2003), it is also possible that many of these are also expressed in a sex-specific fashion and are important for androgenic modulation of angiogenesis.

Bottom Line: Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs.In vivo, castration dramatically reduced neovascularization of Matrigel plugs.Androgen treatment fully reversed this effect in male mice but had no effect in female mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Heart Research Institute, Sydney 2042, Australia. sievekingd@hri.org.au

ABSTRACT
Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.

Show MeSH
Related in: MedlinePlus