Pericyte-Derived Dickkopf2 Regenerates Damaged Penile Neurovasculature Through an Angiopoietin-1-Tie2 Pathway

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Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is amajor cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that the overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function. Transcriptome analysis revealed that angiopoietin-1 and angiopoietin-2 are target genes for DKK2. Using an endothelial cell-pericyte co-culture system and ex vivo neurite sprouting assay, we found that DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes angiogenesis and neural regeneration through an angiopoietin-1-Tie2 pathway, rescuing erectile function in diabetic mice. The dual angiogenic and neurotrophic effects of DKK2, especially as a therapeutic protein, will open new avenues to treating diabetic ED.
Publisher
AMER DIABETES ASSOC
Issue Date
2018-06
Language
English
Article Type
Article
Keywords

ENDOTHELIAL GROWTH-FACTOR; RESTORES ERECTILE FUNCTION; MOUSE CORPUS CAVERNOSUM; NEUROTROPHIC FACTOR; SIGNALING PATHWAY; DIABETIC MOUSE; GENE-THERAPY; DYSFUNCTION; CELLS; ANGIOGENESIS

Citation

DIABETES, v.67, no.6, pp.1149 - 1161

ISSN
0012-1797
DOI
10.2337/db17-0833
URI
http://hdl.handle.net/10203/244902
Appears in Collection
MSE-Journal Papers(저널논문)
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