A new role for corticotropin-releasing factor receptor-2: suppression of vascularization.
The corticotropin-releasing factor (CRF) family of receptors and ligands are known to have potent effects on vasculature function. Our recent data has described a novel role of corticotropin-releasing factor receptor-2 (CRFR2) as a tonic inhibitor of neovascularization. CRFR2 is found in both endothelial and smooth muscle cells (SMC) in the vasculature, where its function has been elusive. From investigation into the role of CRFR2 as a determinant of tissue vascularization, it was discovered that mice deficient for CRFR2 become hypervascularized postnatally and express increased levels of vascular endothelial growth factor (VEGF). Mechanistically, CRFR2 activation in vitro was found to result in reduced VEGF release from SMCs, an inhibition of SMC proliferation, and an inhibition of capillary tube formation in collagen gels. Treatment of a subcutaneously injected gel matrix with a CRFR2 agonist inhibited growth factor-induced vascularization in vivo. Western blots for the cell-cycle retinoblastoma protein (Rb)--essential for cell-cycle progression, showed decreased levels of phosphorylated Rb following CRFR2 agonist treatment in SMCs--supporting a role for CRFR2 in regulation of SMC proliferation. These results suggest that CRFR2 is a critical component of a novel pathway necessary for tonic inhibition of adult neovascularization, and that CRFR2 may be a potential target for therapeutic modulation of angiogenesis.
Bale
Tracy L
TL
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA. bale@salk.edu
Giordano
Frank J
FJ
Vale
Wylie W
WW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology* / Q000627:therapeutic use; D014664:Vasodilation / Q000187:drug effects
C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone