Sildenafil promotes smooth muscle preservation and ameliorates fibrosis through modulation of extracellular matrix and tissue growth factor gene expression after bilateral cavernosal nerve resection in the rat.
BACKGROUND
It has been shown that phosphodiesterase type 5 (PDE5) inhibitors preserve smooth muscle (SM) content and ameliorate the fibrotic degeneration normally seen in the corpora cavernosa after bilateral cavernosal nerve resection (BCNR). However, the downstream mechanisms by which these drugs protect the corpora cavernosa remain poorly understood.


OBJECTIVE
To provide insight into the mechanism, we aimed to determine the gene expression profile of angiogenesis-related pathways within the penile tissue after BCNR with or without continuous sildenafil (SIL) treatment.


METHODS
Five-month-old Fisher rats were subjected to BCNR or sham operation and treated with or without SIL (20 mg/kg/BW drinking water) for 3 days or 45 days (N = 8 rats per group). Total RNAs isolated from the denuded penile shaft and prostate were subjected to reverse transcription and to angiogenesis real-time-polymerase chain reaction arrays (84 genes). Changes in protein expression of selected genes such as epiregulin (EREG) and connective tissue growth factor (CTGF) were corroborated by Western blot and immunohistochemistry.


METHODS
Genes modulated by BCNR and SIL treatment.


RESULTS
A decreased expression of genes related to SM growth factors such as EREG, platelet-derived growth factor (PDGF), extracellular matrix regulators such as metalloproteinases 3 and 9, endothelial growth factors, together with an upregulation of pro-fibrotic genes such as CTGF and transforming growth factor beta 2 were found at both time points after BCNR. SIL treatment reversed this process by upregulating endothelial and SM growth factors and downregulating pro-fibrotic factors. SIL did not affect the expression of EREG, VEGF, and PDGF in the ventral prostate of BCNR animals.


CONCLUSIONS
SIL treatment after BCNR activates genes related to SM preservation and downregulates genes related to fibrosis in the corpora cavernosa. These results provide a mechanistic justification for the use of SIL and other PDE5 inhibitors as protective therapy against corporal SM loss and fibrosis after radical prostatectomy.
Department of Internal Medicine, Charles R. Drew University of Medicine & Science, Los Angeles, CA, USA.
Fara
F
Sirad
Su
S
Hlaing
Istvan
I
Kovanecz
Jorge N
JN
Artaza
Leah A
LA
Garcia
Jacob
J
Rajfer
Monica G
MG
Ferrini
D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000187:drug effects; D066260:Epiregulin; D005109:Extracellular Matrix / Q000187:drug effects*; D005355:Fibrosis / Q000188:drug therapy* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects; D009417:Nerve Tissue / Q000293:injuries; D010413:Penis / Q000098:blood supply / Q000294:innervation / Q000601:surgery*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000187:drug effects / Q000235:genetics
D066260:Epiregulin; C587882:Ereg protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D053781:Transforming Growth Factor beta2; D004815:Epidermal Growth Factor; D000068677:Sildenafil Citrate; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1
Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v8-9
18784153
Respir Res. 2009 Apr 29;10:30
19402887
Mol Pharmacol. 2005 Jul;68(1):226-32
15851653
Growth Factors. 2002 Jun;20(2):61-9
12148564
J Urol. 2004 Feb;171(2 Pt 1):771-4
14713808
Int J Impot Res. 2008 Sep-Oct;20(5):479-86
18650827
J Cell Physiol. 2007 Apr;211(1):197-204
17226792
Biochemistry (Mosc). 2008 Jul;73(7):751-62
18707583
Biol Reprod. 2007 May;76(5):915-23
17287493
J Cell Biochem. 2003 Aug 15;89(6):1126-37
12898511
Eur Urol. 2009 Feb;55(2):334-47
18986755
J Sex Med. 2010 Dec;7(12):3868-78
20487237
Br J Urol. 1984 Dec;56(6):694-7
6534493
J Androl. 2003 Mar-Apr;24(2):239-45
12634311
Eur Urol. 2008 Oct;54(4):924-31
18640769
J Sex Med. 2009 Feb;6(2):415-28
19138364
J Urol. 2005 Oct;174(4 Pt 1):1493-6
16145478
Int J Impot Res. 2008 Mar-Apr;20(2):202-12
17882231
J Androl. 2010 Jul-Aug;31(4):324-35
19926883
Kidney Int. 2002 Aug;62(2):401-11
12110001
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1633-8
9990076
BJU Int. 2008 Jan;101(2):203-10
17888043
Circulation. 2003 Nov 18;108(20):2524-9
14581411
Int J Impot Res. 2008 Jan-Feb;20(1):60-7
17703219
J Sex Med. 2008 Nov;5(11):2502-18
18761597
Curr Opin Urol. 2010 May;20(3):234-40
20224415
J Steroid Biochem Mol Biol. 2010 Mar;119(1-2):73-83
20064609
Nitric Oxide. 2002 May;6(3):283-94
12009846
Biochem Biophys Res Commun. 2001 Feb 23;281(2):373-7
11181057
J Endocrinol. 2009 Feb;200(2):207-21
19036760
Am J Physiol Renal Physiol. 2007 Jul;293(1):F219-26
17389679
Pediatr Res. 2005 Jan;57(1):22-7
15531735
J Sex Med. 2009 Feb;6(2):303-13
19138365
J Sex Med. 2006 May;3(3):419-31
16681467
J Sex Med. 2009 May;6(5):1270-83
19210708
Circ Res. 2003 May 2;92(8):827-39
12730128
Nat Rev Urol. 2009 Aug;6(8):415-27
19657376
Urology. 2006 Aug;68(2):429-35
16904479
J Biol Chem. 2008 Oct 24;283(43):29572-85
18723505
J Endourol. 2008 Sep;22(9):2025-7; discussion 2035
18811529
J Androl. 2008 Jan-Feb;29(1):3-14
17942972
J Sex Med. 2010 Sep;7(9):3033-44
20626593
J Endocrinol. 2008 Feb;196(2):235-49
18252947
J Biol Chem. 2005 May 13;280(19):19012-20
15753092
Curr Pharm Des. 2009;15(30):3496-501
19860695
Biofactors. 2009 Mar-Apr;35(2):200-8
19449449
BJU Int. 2010 Jan;105(1):114-20
19493269
J Sex Med. 2009 Oct;6(10):2813-9
19686421
Curr Opin Investig Drugs. 2008 Jul;9(7):754-9
18600581