Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction
ShengPeng Wang, … , Nina Wettschureck, Stefan Offermanns
ShengPeng Wang, … , Nina Wettschureck, Stefan Offermanns
Published July 13, 2015
Citation Information: J Clin Invest. 2015;125(8):3077-3086. https://doi.org/10.1172/JCI81067.
View: Text | PDF
Research Article Vascular biology

P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction

  • Text
  • PDF
Abstract

Elevated blood pressure is a key risk factor for developing cardiovascular diseases. Blood pressure is largely determined by vasodilatory mediators, such as nitric oxide (NO), that are released from the endothelium in response to fluid shear stress exerted by the flowing blood. Previous work has identified several mechanotransduction signaling processes that are involved in fluid shear stress–induced endothelial effects, but how fluid shear stress initiates the response is poorly understood. Here, we evaluated human and bovine endothelial cells and found that the purinergic receptor P2Y2 and the G proteins Gq/G11 mediate fluid shear stress–induced endothelial responses, including [Ca2+]i transients, activation of the endothelial NO synthase (eNOS), phosphorylation of PECAM-1 and VEGFR-2, as well as activation of SRC and AKT. In response to fluid shear stress, endothelial cells released ATP, which activates the purinergic P2Y2 receptor. Mice with induced endothelium-specific P2Y2 or Gq/G11 deficiency lacked flow-induced vasodilation and developed hypertension that was accompanied by reduced eNOS activation. Together, our data identify P2Y2 and Gq/G11 as a critical endothelial mechanosignaling pathway that is upstream of previously described mechanotransduction processes and demonstrate that P2Y2 and Gq/G11 are required for basal endothelial NO formation, vascular tone, and blood pressure.

Authors

ShengPeng Wang, András Iring, Boris Strilic, Julián Albarrán Juárez, Harmandeep Kaur, Kerstin Troidl, Sarah Tonack, Joachim C. Burbiel, Christa E. Müller, Ingrid Fleming, Jon O. Lundberg, Nina Wettschureck, Stefan Offermanns

×

Figure 1

Gq and G11 mediate endothelial response to fluid shear stress in vitro.

Options: View larger image (or click on image) Download as PowerPoint
Gq and G11 mediate endothelial response to fluid shear stress in vitro.
...
The indicated cells were transfected with scrambled (control) siRNA, or an siRNA directed against Gαq and Gα11. (A) Fluo-4–loaded HUVECs (n = 21, control; n = 25, Gαq/11; 3 independent experiments) and BAECs (n = 23, control; n = 16, Gαq/11; 3 independent experiments) were exposed to the indicated shear forces, and [Ca2+]i was determined as fluorescence intensity (RFU, relative fluorescence units). Graphs show the AUC. Data represent the mean ± SEM; ***P ≤ 0.001, by 2-tailed Student’s t test. (B–D) HUVECs and BAECs (n = 3) were exposed to fluid shear (12 and 20 dynes/cm2, respectively) for the indicated durations. AKT, eNOS, and SRC activation (B and D) was determined by Western blotting for phosphorylated AKT, eNOS, and SRC kinases and total AKT, eNOS, and SRC. PECAM-1 and VEGFR-2 activation (D) was determined by IP and Western blotting for tyrosine phosphorylated PECAM-1 and VEGFR-2 . Knockdown of Gαq/Gα11 was verified by anti-Gαq/Gα11 immunoblotting. Graphs show the densitometric evaluation. C, Nitrate concentration in the cell medium. Data represent the mean ± SEM; *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001, by 2-way ANOVA, with Bonferroni’s post-hoc test. p, phosphorylated; S, serine.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts