Inactivation of BACE1 increases expression of endothelial nitric oxide synthase in cerebrovascular endothelium

Tongrong D He, Livius V. d’Uscio, Ruohan Sun, Anantha V Santhanam, Zvonimir S. Katusic

Research output: Contribution to journalArticlepeer-review

Abstract

Cerebrovascular effects of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inactivation have not been systematically studied. In the present study we employed cultured human brain microvascular endothelial cells (BMECs), BACE1-knockout (BACE1−/−) mice and conditional (tamoxifen-induced) endothelium-specific BACE1-knockout (eBACE1−/−) mice to determine effect of BACE1 inhibition on expression and function of endothelial nitric oxide synthase (eNOS). Deletion of BACE1 caused upregulation of eNOS and glypican-1 (GPC1) in human BMECs treated with BACE1-siRNA, and cerebral microvessels of male BACE1−/− mice and male eBACE1−/− mice. In addition, BACE1siRNA treatment increased NO production in human BMECs. These effects appeared to be independent of amyloid β-peptide production. Furthermore, adenoviral-mediated overexpression of BACE1 in human BMECs down-regulated GPC1 and eNOS. Treatment of human BMECs with GPC1siRNA suppressed mRNA and protein levels of eNOS. In basilar arteries of male eBACE1−/− mice, endothelium-dependent relaxations to acetylcholine and endothelium-independent relaxations to NO donor, DEA-NONOate, were not affected, consistent with unchanged expression of eNOS and phosphorylation of eNOS at Ser1177 in large cerebral arteries. In aggregate, our findings suggest that under physiological conditions, inactivation of endothelial BACE1 increases expression of eNOS in cerebral microvessels but not in large brain arteries. This effect appears to be mediated by increased GPC1 expression.

Original languageEnglish (US)
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
StateAccepted/In press - 2022

Keywords

  • Alzheimer’s disease
  • BACE1
  • endothelial cells
  • eNOS
  • glypican-1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Inactivation of BACE1 increases expression of endothelial nitric oxide synthase in cerebrovascular endothelium'. Together they form a unique fingerprint.

Cite this