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

Diabetes. 2018 Jun;67(6):1149-1161. doi: 10.2337/db17-0833. Epub 2018 Mar 20.

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.

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