Back to Search
Start Over
Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling
- Source :
- Circulation. 128:60-71
- Publication Year :
- 2013
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2013.
-
Abstract
- Background— Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in response to ischemia. Methods and Results— Both male and female AR knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of AR knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor ( VEGF ) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components. Conclusions— These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.
- Subjects :
- Male
medicine.medical_specialty
Nitric Oxide Synthase Type III
Angiogenesis
Proto-Oncogene Proteins pp60(c-src)
Neovascularization, Physiologic
Apoptosis
Article
Mice
Phosphatidylinositol 3-Kinases
Ischemia
Physiology (medical)
Internal medicine
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Feminization
Muscle, Skeletal
Protein kinase B
Mice, Knockout
business.industry
Akt/PKB signaling pathway
Amputation Stumps
Kinase insert domain receptor
Receptor Cross-Talk
Vascular Endothelial Growth Factor Receptor-2
Capillaries
Hindlimb
Androgen receptor
Vascular endothelial growth factor B
Vascular endothelial growth factor A
Endocrinology
Receptors, Androgen
Female
Cardiology and Cardiovascular Medicine
business
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 15244539 and 00097322
- Volume :
- 128
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi.dedup.....93c5177f49ca085cb27e281f739c3e4c