ZFIN ID: ZDB-PUB-100309-24
A{beta} peptides accelerate the senescence of endothelial cells in vitro and in vivo, impairing angiogenesis
Donnini, S., Solito, R., Cetti, E., Corti, F., Giachetti, A., Carra, S., Beltrame, M., Cotelli, F., and Ziche, M.
Date: 2010
Source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology   24(7): 2385-2395 (Journal)
Registered Authors: Beltrame, Monica, Cotelli, Franco
Keywords: none
MeSH Terms:
  • Amyloid beta-Peptides/genetics
  • Amyloid beta-Peptides/pharmacology
  • Amyloid beta-Peptides/toxicity*
  • Angiogenesis Inhibitors
  • Animals
  • Blood Vessels/growth & development
  • Blood Vessels/pathology
  • Cellular Senescence/drug effects*
  • Cerebral Amyloid Angiopathy
  • Embryo, Nonmammalian/drug effects
  • Endothelial Cells/drug effects*
  • Endothelial Cells/pathology
  • Endothelial Cells/physiology
  • Endothelium, Vascular/pathology
  • Humans
  • Mutation, Missense
  • Neovascularization, Physiologic/drug effects
  • Survival Rate
  • Zebrafish
PubMed: 20207941 Full text @ FASEB J.
ABSTRACT
Cerebral amyloid angiopathy (CAA) caused by amyloid beta (Abeta) deposition around brain microvessels results in vascular degenerative changes. Antiangiogenic Abeta properties are known to contribute to the compromised cerebrovascular architecture. Here we hypothesize that Abeta peptides impair angiogenesis by causing endothelial cells to enter senescence at an early stage of vascular development. Wild-type (WT) Abeta and its mutated variant E22Q peptide, endowed with marked vascular tropism, were used in this study. In vivo, in zebrafish embryos, the WT or E22Q peptides reduced embryo survival with an IC50 of 6.1 and 4.7 muM, respectively. The 2.5 muM concentration, showing minimal toxicity, was chosen. Alkaline phosphatase staining revealed disorganized vessel patterning, narrowing, and reduced branching of vessels. beta-Galactosidase staining and the cyclin-dependent kinase inhibitor p21 expression, indicative of senescence, were increased. In vitro, WT and E22Q reduced endothelial cell survival with an IC50 of 12.3 and 8.8 muM, respectively. The 5 muM concentration, devoid of acute effects on the endothelium, was applied chronically to long-term cultured human umbilical vein endothelial cells (HUVECs). We observed reduced cumulative population doubling, which coincided with beta-galactosidase accumulation, down-regulation of telomerase reverse-transcriptase mRNA expression, decreased telomerase activity, and p21 activation. Senescent HUVECs showed marked angiogenesis impairment, as Abeta treatment reduced tube sprouting. The endothelial injuries caused by the E22Q peptide were much more aggressive than those induced by the WT peptide. Premature Abeta-induced senescence of the endothelium, producing progressive alterations of microvessel morphology and functions, may represent one of the underlying mechanisms for sporadic or heritable CAA.
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