The Aβ peptides-activated calcium-sensing receptor stimulates the production and secretion of vascular endothelial growth factor-A by normoxic adult human cortical astrocytes

Neuromolecular Med. 2014 Dec;16(4):645-57. doi: 10.1007/s12017-014-8315-9. Epub 2014 Jun 20.


The excess vascular endothelial growth factor (VEGF) produced in the Alzheimer's disease (AD) brain can harm neurons, blood vessels, and other components of the neurovascular units (NVUs). But could astrocytes partaking in networks of astrocyte-neuron teams and connected to blood vessels of NVUs contribute to VEGF production? We have shown with cultured cerebral cortical normal (i.e., untransformed) adult human astrocytes (NAHAs) that exogenous amyloid-β peptides (Aβs) stimulate the astrocytes to make and secrete large amounts of Aβs and nitric oxide by a mechanism mediated through the calcium-sensing receptor (CaSR). Here, we report that exogenous Aβs stimulate the NAHAs to produce and secrete even VEGF-A through a CaSR-mediated mechanism. This is indicated by the ability of Aβs to specifically bind the CaSR, and the capability of a CaSR activator, the "calcimimetic" NPS R-568, to imitate, and of the CaSR antagonist, "calcilytic" NPS 2143, to inhibit, the Aβs stimulation of VEGF-A production and secretion by the NAHAs. Thus, Aβs that accumulate in the AD brain may make the astrocytes that envelop and functionally collaborate with neurons into multi-agent AD-driving "machines" via a CaSR signaling mechanism(s). These observations suggest the possibility that CaSR allosteric antagonists such as NPS 2143 might impede AD progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allosteric Regulation
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / pharmacology*
  • Aniline Compounds / pharmacology
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Calcium / agonists
  • Cell Communication
  • Cells, Cultured
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Naphthalenes / pharmacology
  • Neurons / metabolism
  • Nitric Oxide / metabolism
  • Peptide Fragments / pharmacology*
  • Phenethylamines
  • Propylamines
  • Protein Binding
  • Receptors, Calcium-Sensing / antagonists & inhibitors
  • Receptors, Calcium-Sensing / physiology*
  • Temporal Lobe / cytology
  • Vascular Endothelial Growth Factor A / biosynthesis*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Amyloid beta-Peptides
  • Aniline Compounds
  • CASR protein, human
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
  • N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
  • Naphthalenes
  • Peptide Fragments
  • Phenethylamines
  • Propylamines
  • Receptors, Calcium-Sensing
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • amyloid beta-protein (1-42)
  • amyloid beta-protein (25-35)
  • Nitric Oxide
  • Calcium