Abstract
Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is a major 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 coculture 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.
© 2018 by the American Diabetes Association.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adult
-
Angiopoietin-1 / agonists*
-
Angiopoietin-1 / genetics
-
Angiopoietin-1 / metabolism
-
Animals
-
Cell Line, Tumor
-
Cells, Cultured
-
Coculture Techniques
-
Crosses, Genetic
-
Diabetes Mellitus, Type 1 / complications
-
Diabetes Mellitus, Type 1 / metabolism*
-
Diabetes Mellitus, Type 1 / pathology
-
Diabetes Mellitus, Type 2 / complications
-
Diabetes Mellitus, Type 2 / metabolism
-
Diabetes Mellitus, Type 2 / pathology
-
Diabetic Angiopathies / drug therapy
-
Diabetic Angiopathies / metabolism
-
Diabetic Angiopathies / pathology
-
Diabetic Nephropathies / drug therapy
-
Diabetic Nephropathies / metabolism
-
Diabetic Nephropathies / pathology
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / innervation
-
Endothelium, Vascular / metabolism*
-
Endothelium, Vascular / pathology
-
Erectile Dysfunction / complications
-
Erectile Dysfunction / drug therapy
-
Erectile Dysfunction / metabolism
-
Erectile Dysfunction / pathology
-
Humans
-
Intercellular Signaling Peptides and Proteins / chemistry
-
Intercellular Signaling Peptides and Proteins / genetics
-
Intercellular Signaling Peptides and Proteins / metabolism*
-
Intercellular Signaling Peptides and Proteins / therapeutic use
-
Male
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Penis / blood supply
-
Penis / innervation
-
Penis / metabolism*
-
Penis / pathology
-
Pericytes / drug effects
-
Pericytes / metabolism*
-
Pericytes / pathology
-
Receptor, TIE-2 / agonists*
-
Receptor, TIE-2 / metabolism
-
Wnt Signaling Pathway
-
Young Adult
Substances
-
Angiopoietin-1
-
Angpt1 protein, mouse
-
DKK2 protein, human
-
Dkk2 protein, mouse
-
Intercellular Signaling Peptides and Proteins
-
Receptor, TIE-2
-
Tek protein, mouse