eNOS-NO-induced small blood vessel relaxation requires EHD2-dependent caveolae stabilization

PLoS One. 2019 Oct 10;14(10):e0223620. doi: 10.1371/journal.pone.0223620. eCollection 2019.

Abstract

Endothelial nitric oxide synthase (eNOS)-related vessel relaxation is a highly coordinated process that regulates blood flow and pressure and is dependent on caveolae. Here, we investigated the role of caveolar plasma membrane stabilization by the dynamin-related ATPase EHD2 on eNOS-nitric oxide (NO)-dependent vessel relaxation. Loss of EHD2 in small arteries led to increased numbers of caveolae that were detached from the plasma membrane. Concomitantly, impaired relaxation of mesenteric arteries and reduced running wheel activity were observed in EHD2 knockout mice. EHD2 deletion or knockdown led to decreased production of nitric oxide (NO) although eNOS expression levels were not changed. Super-resolution imaging revealed that eNOS was redistributed from the plasma membrane to internalized detached caveolae in EHD2-lacking tissue or cells. Following an ATP stimulus, reduced cytosolic Ca2+ peaks were recorded in human umbilical vein endothelial cells (HUVECs) lacking EHD2. Our data suggest that EHD2-controlled caveolar dynamics orchestrates the activity and regulation of eNOS/NO and Ca2+ channel localization at the plasma membrane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / physiology*
  • Calcium / metabolism
  • Carrier Proteins / metabolism*
  • Caveolae / metabolism*
  • Caveolae / ultrastructure
  • Cell Membrane / metabolism
  • Cytosol / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Mesenteric Arteries / diagnostic imaging
  • Mesenteric Arteries / metabolism
  • Mice, Inbred C57BL
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / metabolism*
  • Physical Conditioning, Animal
  • Vasodilation / physiology*

Substances

  • Carrier Proteins
  • EHD2 protein, human
  • EHD2 protein, mouse
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Calcium

Grants and funding

This work was supported by- to OD: Sonderforschungsbereich SFB958, project A12, http://www.sfb958.de/, Helmholtz-Gemeinschaft, Initiative and Networking Fund. To MG: Deutsche Forschungsgemeinschaft DFG research grant 318527103, http://gepris.dfg.de/gepris/person/1421037?context=person&task=showDetail&id=1421037&. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.