title: Androgen Receptor-Mediated Genomic Androgen Action Augments Ischemia-Induced Neovascularization.
abstract: Increasing evidence indicates that androgens regulate ischemia-induced neovascularization. However, the role of genomic androgen action mediated by androgen receptor (AR), a ligand-activated nuclear transcription factor, remains poorly understood. Using an AR knockout (KO) mouse strain that contains a transcriptionally inactive AR (ARΔex3KO), we examined the role of AR genomic function in modulating androgen-mediated augmentation of ischemia-induced neovascularization. Castrated wild-type (ARWT) and ARΔex3KO mice were implanted with 5α-dihydrotestosterone (DHT) or placebo pellets after hindlimb ischemia (HLI). DHT modulation of angiogenesis and vasculogenesis, key processes for vascular repair and regeneration, was examined. Laser Doppler perfusion imaging revealed that DHT enhanced blood flow recovery in ARWTmice post-HLI. In ARWTmice, DHT enhanced angiogenesis by down-regulating prolyl hydroxylase 2 and augmenting hypoxia-inducible factor-1α (HIF-1α) levels in the ischemic tissues post-HLI. DHT also enhanced the production and mobilization of Sca1+/CXCR4+ progenitor cells in the bone marrow (BM) and circulating blood, respectively, in ARWTmice. By contrast, DHT-mediated enhancement of blood flow recovery was abrogated in ARΔex3KO mice. DHT modulation of HIF-1α expression was attenuated in ARΔex3KO mice. DHT-induced HIF-1α transcriptional activity and DHT-augmented paracrine-mediated endothelial cell tubule formation were attenuated in fibroblasts isolated from ARΔex3KO mice in vitro. Furthermore, DHT-induced augmentation of Sca1+/CXCR4+ progenitor cell production and mobilization was absent in ARΔex3KO mice post-HLI. BM transplantation revealed that ischemia-induced mobilization of circulating progenitor cells was abolished in recipients of ARΔex3KO BM. Together, these results indicate that androgen-mediated augmentation of ischemia-induced neovascularization is dependent on genomic AR transcriptional activation.
authors.affiliation: The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
authors.forename: Yuen Ting
authors.initials: YT
authors.lastname: Lam
authors.affiliation: The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Lecce
authors.affiliation: The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
authors.forename: Joanne T M
authors.initials: JT
authors.lastname: Tan
authors.affiliation: The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bursill
authors.affiliation: The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.affiliation: The Heart Research Institute (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School (Y.T.L., L.L., J.T.M.T., C.A.B., M.K.C.N.), The University of Sydney, Sydney, New South Wales 2006, Australia; ANZAC Research Institute (D.J.H.), The University of Sydney, Concord Hospital, Sydney, New South Wales 2139, Australia; and Department of Cardiology (M.K.C.N.), Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia.
authors.forename: Martin K C
authors.initials: MK
authors.lastname: Ng
mesh_terms: D000728:Androgens; D000818:Animals; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply*; D061307:Human Umbilical Vein Endothelial Cells; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D000728:Androgens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011944:Receptors, Androgen