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Have you read ? Best of the Best: Basic Research
Diabetic ED – Role of fibrosis
Shin SH, Kim WJ, Choi MJ, Park JM, Jin HR,
Yin GN, Ryu JK, Suh JK:
Aberrant expression
of Wnt family contributes to the pathogenesis
of diabetes-induced erectile dysfunction.
Andrology 2013, doi: 10.1002/term.1806 /
Nov 21 [Epub ahead of print].
Li WJ, Wang H, Zhou J, Li B, Zhang J, Lu M,
Wang Z:
P144, a TGF-ß1 antagonist peptide,
synergizes with sildenafil and enhances
erectile responses via amelioration of cav-
ernosal fibrosis in diabetic rats.
J Sexual Med 2013, doi: 10.1111/jsm.12325 /
Oct 17 [Epub ahead of print].
Recently, a key role of morphogen and stem
cell pathways in fibrotic diseases has been
suggested. These pathways include Notch,
Hedgehog and Wnt pathways. Wnt signaling is
fundamental in embryonic development and also
in stem cell renewal and tissue homeostasis in
adults. Canonical Wnt pathway involves bind-
ing to Frizzled receptors which, once activated,
prevent degradation of ß-catenin allowing its
nuclear translocation and transcription of target
genes. Aberrant activation of Wnt signaling has
been suggested to be a common denomina-
tor in fibrotic diseases. Wnt activation in vitro
stimulates the differentiation of resting fibro-
blasts into myofibroblasts and increases the
secretion of extracellular matrix proteins while
in vivo results in rapid and progressive fibrosis. In
addition, Wnt signaling interacts with transform-
ing growth factor-ß (TGF-ß) another important
profibrotic pathway. Inhibition of TGF-ß reduces
Wnt signaling while disruption of Wnt pathway
prevents the ability of TGF-ß to promote fibrosis.
On the other hand, functional alterations of
cavernosal tissue and penile arteries caused
by diabetes ultimately result in structural and
morphological alterations such as fibrosis which
account for the development of erectile dysfunc-
tion (ED) and, possibly, for the reduced response
to PDE5 inhibitors in diabetes. The two recent
papers here commented have analyzed the
implication of Wnt and TGF-ß signaling in ED
caused by diabetes in rodents and its thera-
peutic implications.
Shin and collaborators
studied the expres-
sion of Wnt proteins in the penile tissue from
mice with streptozotocin-induced diabetes.
Sixteen different Wnt proteins were detected
in corpus cavernosum from mice and 14 Wnts
were detected in human fibroblasts derived from
tunica albuginea. Up-regulation of Wnt10b and
down-regulation of Wnt16 was observed in cav-
ernosal tissue from diabetic mice together with
increased TGF-ß1 protein expression, reduced
endothelial content and increased cavernosal
fibrosis. Wnt10b is known to contribute to fibrotic
processes while Wnt16 has been suggested to
be involved in hematopoiesis and to influence
bone mineral density. Stimulation of human fibro-
blasts with TGF-ß1 also results in up-regulation
of Wnt10b and down-regulation of Wnt16. How-
ever, inhibition of Wnt10b expression did not
decrease the production of extracellular matrix
proteins in these cells. In contrast, overexpres-
sion of Wnt16 in cultured cavernosal endothelial
cells from mice enhanced angiogenic phenotype.
On the other hand,
Li and co-workers
evalu-
ated inhibition of TGF-ß1 on erectile function
and cavernosal structure in streptozotocin-
induced diabetic rats and its influence on
the response to PDE5 inhibition. Ten weeks
of diabetes resulted in decreased erectile
responses, severe corporal veno-occlusive
dysfunction (CVOD), cavernosal fibrosis and
decreased smooth muscle content. This was
accompanied by an elevation in expression
and activation of TGF-ß1 and downstream
proteins. Treatment of 6-weeks diabetic rats
for 4 additional weeks with sildenafil mod-
estly improved diabetes-induced alterations
in erectile function and cavernosal structure.
Treatment for the same period with P144, a
peptide antagonizing TGF-ß1, although had
marginal effect on erectile responses greatly
improved histological alterations of cavernosal
tissue and relieved CVOD. Combined adminis-
tration of P144 and sildenafil restored erectile
responses, reversed CVOD and normalized
cavernosal histology.
These research works point to a role of Wnt
and TGF-ß1 pathways in cavernosal fibrosis
accompanying diabetic ED, suggesting that
inhibition of these pathways would prevent/
reverse fibrosis and improve erectile func-
tion and/or the response to conventional
therapy (i.e. PDE5 inhibitors) in diabetes
.
P144 is a peptide that could have adminis-
tration limitations while some small molecule
inhibitors of Wnt signaling have entered in
clinical development. However, the role of
Wnt
proteins in tissue homeostasis and stem
cell renewal
, together with the fact that
Wnt
signaling differ in tissue-, cell type-, and
environment-specific manner
, prompt to
carefully watching potential side effects
of
this therapeutic strategy.
