Proangiogenetic molecules, hypoxia-inducible factor-1alpha and nitric oxide synthase isoforms in ovarian endometriotic cysts.
Endometriosis is a common disease characterised by ectopic growth of endometrial tissue outside the uterine cavity. Angiogenesis has been implicated in the pathogenesis of the disease; some molecules, like hypoxia-inducible factor-1alpha (HIF-1alpha) and neuronal, endothelial and inducible nitric oxide synthase isoforms (nNOS, eNOS and iNOS), are known as proangiogenetic factors. We evaluated expression of these molecules by immunohistochemistry in 32 cases of ovarian endometriomas, formalin-fixed and paraffin-embedded. Analysis was focused on the cells composing the inner layer of the cyst, constituted by the ectopic endometrial glands, stromal cells and vessels, and the outer one, constituted by a fibrous layer of fibroblasts and vessels. We found that epithelial glands and capsular vessel endothelial cells showed a correlated expression of NOS isoforms; that expression of nNOS, iNOS and HIF-1alpha was correlated in epithelial glands and capsular fibroblasts; that vessel endothelial cells showed a higher mean expression for all the proangiogenetic molecules in the outer layer than in the inner one; and that capsular fibroblasts showed a higher mean expression for HIF-1alpha, iNOS and eNOS compared to the specialised stromal cells of the inner layer. Our data seem to indicate that angiogenesis is stimulated more in the outer capsule than in the inner layer of ovarian endometriotic cysts. The knowledge of the complex mechanisms associated to angiogenesis might be useful in a therapeutic approach of ovarian endometriosis based on anti-angiogenetic drugs. The therapeutic target would be mainly the capsular vasculature, more than the vasculature of ectopic endometrial tissues.
Goteri
Gaia
G
Section of Anatomic Pathology, Department of Neurosciences, Polytechnic University of Marche Region, Via Conca, 71, 60020, Torrette di Ancona, Italy. g.goteri@univpm.it
Lucarini
Guendalina
G
Zizzi
Antonio
A
Rubini
Corrado
C
Di Primio
Roberto
R
Tranquilli
Andrea Luigi
AL
Ciavattini
Andrea
A
D000328:Adult; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic / Q000209:etiology; D019001:Nitric Oxide Synthase / Q000032:analysis*; D052248:Nitric Oxide Synthase Type I / Q000032:analysis; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D010048:Ovarian Cysts / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
Int J Clin Oncol. 2009 Oct;14(5):378-82
19856043
Obstet Gynecol. 1986 Mar;67(3):335-8
3945444
Am J Pathol. 2008 Feb;172(2):534-44
18202195
Endocr Rev. 1997 Feb;18(1):4-25
9034784
Endocrinology. 2006 Jan;147(1):232-46
16195411
Am J Pathol. 2007 Feb;170(2):590-8
17255327
Mol Hum Reprod. 1997 Jan;3(1):69-75
9239710
Pharmacol Rev. 1991 Jun;43(2):109-42
1852778
Fertil Steril. 2004 Jun;81(6):1528-33
15193472
Int J Clin Oncol. 2009 Oct;14(5):383-91
19856044
Hum Reprod. 2003 Dec;18(12):2668-71
14645189
Fertil Steril. 2007 Aug;88(2):513-5
17296185
Angiogenesis. 2005;8(2):147-56
16211360
Lancet. 2004 Nov 13-19;364(9447):1789-99
15541453
Fertil Steril. 2006 Apr;85(4):1037-44
16580392
J Biol Chem. 2001 Jan 19;276(3):2292-8
11056166
EMBO J. 1998 Jun 1;17(11):3005-15
9606183
Int J Gynecol Pathol. 2001 Apr;20(2):147-54
11293160
Fertil Steril. 2008 Jul;90(1):148-55
17765237
Biochim Biophys Acta. 2008 Jan;1784(1):150-8
17964232
Anticancer Res. 2005 Nov-Dec;25(6B):4313-8
16309234
Cell. 1994 Sep 23;78(6):915-8
7522969
Fertil Steril. 1998 Feb;69(2):303-8
9496346
Int J Gynecol Pathol. 2009 Mar;28(2):157-63
19188818
Hum Reprod. 1996 Jan;11(1):220-3
8671190
Fertil Steril. 1997 Oct;68(4):585-96
9341595
Acta Histochem. 2009;111(1):61-7
18556049
Hum Reprod. 1998 Jun;13(6):1686-90
9688413
Hum Reprod. 2007 Aug;22(8):2120-7
17609243
Fertil Steril. 2002 Jan;77(1):46-51
11779590
Acta Biochim Pol. 2003;50(1):49-59
12673346
Mol Hum Reprod. 2000 Feb;6(2):185-90
10655461
Biochem J. 1994 Mar 1;298 ( Pt 2):249-58
7510950
Microvasc Res. 2007 Sep-Nov;74(2-3):121-30
17574280
Hum Pathol. 2004 Nov;35(11):1369-75
15668894
Fertil Steril. 2002 Oct;78(4):860-4
12372469
N Engl J Med. 2009 Jan 15;360(3):268-79
19144942
Mol Hum Reprod. 2008 May;14(5):259-68
18430758
Nature. 1992 Oct 29;359(6398):843-5
1279431
N Engl J Med. 1993 Dec 30;329(27):2002-12
7504210
Fertil Steril. 2002 Jul;78(1):148-53
12095505
Fertil Steril. 2008 Oct;90(4):988-93
18053993
Fertil Steril. 2005 Oct;84 Suppl 2:1180-90
16210010
Hum Reprod. 1995 Jan;10(1):19-23
7538147
J Reprod Med. 2001 Oct;46(10):887-91
11725732