Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism.
Growing evidences support that androgen displays beneficial effects on cardiovascular functions although the mechanism of androgen actions remains to be elucidated. Modulation of endothelial cell growth and function is a potential mechanism of androgen actions. We demonstrated in the present study that androgens [dihydrotestosterone (DHT) and testosterone], but not 17β-estradiol, produced a time- and dose-dependent induction of cell proliferation in primary human aortic endothelial cells (HAECs) as evident by increases in viable cell number and DNA biosynthesis. Real-time qRT-PCR analysis showed that DHT induced androgen receptor (AR), cyclin A, cyclin D1, and vascular endothelial growth factor (VEGF) gene expression in a dose- and time-dependent manner. The addition of casodex, a specific AR antagonist, or transfection of a specific AR siRNA blocked DHT-induced cell proliferation and target gene expression, indicating that the DHT effects are mediated via AR. Moreover, coadministration of SU5416 to block VEGF receptors, or transfection of a specific VEGF-A siRNA to knockdown VEGF expression, produced a dose-dependent blockade of DHT induction of cell proliferation and cyclin A gene expression. Interestingly, roscovitine, a selective cyclin-dependent kinase inhibitor, also blocked the DHT stimulation of cell proliferation with a selective inhibition of DHT-induced VEGF-A expression. These results indicate that androgens acting on AR stimulate cell proliferation through upregulation of VEGF-A, cyclin A, and cyclin D1 in HAECs, which may be beneficial to cardiovascular functions since endothelial cell proliferation could assist the repair of endothelial injury/damage in cardiovascular system.
Department of Medicine/Endocrinology, Weill Cornell Medical College, New York, New York 10065, USA.
Jingjing
J
Cai
Yuan
Y
Hong
Chunyan
C
Weng
Chen
C
Tan
Julianne
J
Imperato-McGinley
Yuan-Shan
YS
Zhu
D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019925:Cyclin A / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011944:Receptors, Androgen / Q000096:biosynthesis*; D000077546:Roscovitine; D013739:Testosterone / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D059002:Androgen Receptor Antagonists; D000813:Anilides; D019925:Cyclin A; D007211:Indoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011687:Purines; D011758:Pyrroles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D042461:Vascular Endothelial Growth Factor A; D013196:Dihydrotestosterone; D000077546:Roscovitine; D013739:Testosterone; D004958:Estradiol; C116890:Semaxinib; D004247:DNA; C053541:bicalutamide
Brain Res Mol Brain Res. 1998 Mar 30;55(1):115-25
9645966
Endocrinology. 2004 Oct;145(10):4507-12
15231711
Exp Physiol. 2009 Mar;94(3):311-6
19042980
Baillieres Clin Endocrinol Metab. 1998 Apr;12(1):83-113
9890063
JAMA. 2002 Jul 17;288(3):321-33
12117397
J Androl. 2001 Jul-Aug;22(4):537-48
11451350
Clin Sci (Lond). 2006 Aug;111(2):107-18
16831130
Toxicology. 2008 Mar 12;245(1-2):49-64
18242815
Endocr Rev. 2003 Jun;24(3):313-40
12788802
Heart. 2004 Aug;90(8):871-6
15253956
Science. 1996 Dec 6;274(5293):1672-7
8939849
Cell. 1994 Nov 18;79(4):573-82
7954824
Endocr Rev. 1999 Aug;20(4):501-34
10453356
Horm Res. 2005;63(1):6-14
15564783
Pharmacotherapy. 2008 Dec;28(12):1511-22
19025432
Curr Top Microbiol Immunol. 1999;237:41-57
9893345
Endocr Rev. 2003 Apr;24(2):183-217
12700179
N Engl J Med. 2005 Sep 8;353(10):999-1007
16148285
Heart. 2003 Dec;89(12):1411-5
14617549
Biochem Biophys Res Commun. 1998 Oct 9;251(1):287-90
9790948
Prostate. 2006 Oct 1;66(14):1474-86
16921507
Cellscience. 2005 Apr 28;1(4):27-55
16971966
Hypertension. 1998 Jul;32(1):39-45
9674635
Thromb Res. 1984 May 15;34(4):303-10
6547545
Cancer Res. 2000 Apr 15;60(8):2178-89
10786682
Surg Gynecol Obstet. 1967 May;124(5):1011-7
6022476
Cancer Chemother Pharmacol. 2009 Jan;63(2):303-12
18373093
Acta Haematol. 2001;106(4):148-56
11815711
Thromb Res. 1994 Jun 15;74(6):577-94
8091401
Am J Cardiol. 2003 Aug 15;92(4):400-5
12914869
Clin Cancer Res. 2006 Aug 1;12(15):4720-9
16899623
J Natl Cancer Inst. 2008 Jul 16;100(14):1022-36
18612129
J Clin Endocrinol Metab. 2004 Jul;89(7):3313-8
15240608
Circulation. 1999 Apr 6;99(13):1666-70
10190874
Front Horm Res. 2009;37:91-107
19011291
Endocrinology. 1998 Nov;139(11):4672-8
9794479
Hypertension. 1991 Nov;18(5 Suppl):III76-85
1937690
Circulation. 2000 Oct 17;102(16):1906-11
11034937
Prostate. 2007 Dec 1;67(16):1719-28
17879940
Arch Intern Med. 2006 Aug 14-28;166(15):1660-5
16908801
J Cell Physiol. 2003 Sep;196(3):430-43
12891700
J Endocrinol. 2004 Jan;180(1):97-106
14709148
Circulation. 2003 Oct 28;108(17):2054-9
14581384
Heart. 2003 Feb;89(2):121-2
12527649
Circulation. 2007 Dec 4;116(23):2694-701
18040028
Cold Spring Harb Symp Quant Biol. 2002;67:267-73
12858549
J Clin Endocrinol Metab. 2003 Sep;88(9):4043-54
12970260
JAMA. 1973 Nov 5;226(6):652-7
4356847
Circulation. 2006 May 23;113(20):2425-34
16702472
Curr Pharm Des. 2000 Mar;6(4):379-92
10788588
J Clin Endocrinol Metab. 2006 Nov;91(11):4433-7
16940451
J Clin Endocrinol Metab. 2006 Nov;91(11):4599-602
16926245
J Am Geriatr Soc. 2003 Jan;51(1):101-15; discussion 115
12534854
J Clin Endocrinol Metab. 2006 May;91(5):1691-7
16492703
J Exp Med. 2010 Feb 15;207(2):345-52
20071503
Circulation. 1995 Feb 1;91(3):755-63
7530174
J Clin Endocrinol Metab. 2008 Jan;93(1):68-75
17911176
Front Neuroendocrinol. 2008 May;29(2):182-98
17983646
Am J Cardiol. 2002 Apr 1;89(7):862-4
11909577