Blocking TSP1 Ameliorates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting the TGF-β/SMAD Pathway
Purpose: To examine the role and mechanism of thrombospondin-1 (TSP1) in the development of fibrosis in diabetes mellitus- induced erectile dysfunction (DMED). Materials and Methods: DMED was induced by intraperitoneal streptozotocin injection. All rats were categorized into three groups: control...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Korean Society for Sexual Medicine and Andrology
2025-07-01
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| Series: | The World Journal of Men's Health |
| Subjects: | |
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| Summary: | Purpose: To examine the role and mechanism of thrombospondin-1 (TSP1) in the development of fibrosis in diabetes mellitus-
induced erectile dysfunction (DMED).
Materials and Methods: DMED was induced by intraperitoneal streptozotocin injection. All rats were categorized into three
groups: control group (n=8), DMED group (n=8) and DMED+Leu-Ser-Lys-Leu (LSKL) group (n=8). After eight weeks following
the induction of diabetes mellitus, the DMED+LSKL group was subjected to intraperitoneal injections of LSKL twice weekly
for four weeks. To measure intracavernous pressure (ICP), a 25-gauge needle connected to a PE tube containing heparin was
inserted into the corpus cavernosum (CC). Additionally, a needle was inserted into the carotid artery to measure mean arterial
pressure (MAP). Sirius red staining and Masson trichrome staining were utilized to assess CC fibrosis. Moreover, high glucose
(HG)-induced CC smooth muscle cells (CCSMCs) and CC fibroblasts (CCFs) were treated with or without LSKL. Western blotting
and immunofluorescence were utilized to assess the phosphorylation and expression of related proteins.
Results: Compared with those in the control group, the ratio of the maximum ICP to the MAP markedly decreased in the
DMED group, as did the ratio of smooth muscle to collagen and the ratio of collagen I to collagen III. These ratios were greater
in the DMED+LSKL group than in the DMED group. TSP1 was highly expressed in the CC of DMED rats. In vitro experiments
indicated that TSP1 expression significantly increased in the medium of CCSMCs and CCFs cultured in HG media and
that the TGF-β pathway was activated in CCSMCs. Collagen IV was overexpressed in CCSMCs, indicating severe fibrosis was
severe. Adding LSKL or knocking TSP1 down can prevent the activation of TGF-β signaling, as well as the overexpression of
collagen IV in CCSMCs promoted by TSP1 secreted from CCSMCs itself or CCFs.
Conclusions: TSP1 expression is increased in the CC of DMED rats. HG-induced TSP1 secretion via autocrine signaling from
CCSMCs and/or paracrine signaling from CCFs to accelerate penile fibrosis. LSKL, an antagonist of TSP1, could improve erectile
dysfunction by inhibiting the TGF-β/SMAD pathway. |
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| ISSN: | 2287-4208 2287-4690 |