Heterocellular Contact Can Dictate Arterial Function

Circ Res. 2019 May 10;124(10):1473-1481. doi: 10.1161/CIRCRESAHA.118.313926.


Rationale: Resistance arteries and conduit arteries rely on different relative contributions of endothelial-derived hyperpolarization versus nitric oxide to achieve dilatory heterocellular signaling. Anatomically, resistance arteries use myoendothelial junctions (MEJs), endothelial cell projections that make contact with smooth muscle cells. Conduit arteries have very few to no MEJs.

Objective: Determine if the presence of MEJs in conduit arteries can alter heterocellular signaling.

Methods and results: We previously demonstrated that PAI-1 (plasminogen activator inhibitor-1) can regulate formation of MEJs. Thus, we applied pluronic gel containing PAI-1 directly to conduit arteries (carotid arteries) to determine if this could induce formation of MEJs. We found a significant increase in endothelial cell projections resembling MEJs that correlated with increased biocytin dye transfer from endothelial cells to smooth muscle cells. Next, we used pressure myography to investigate whether these structural changes were accompanied by a functional change in vasodilatory signaling. Interestingly, PAI-1-treated carotids underwent a switch from a conduit to resistance artery vasodilatory profile via diminished nitric oxide signaling and increased endothelial-derived hyperpolarization signaling in response to the endothelium-dependent agonists acetylcholine and NS309. After PAI-1 application, we also found a significant increase in carotid expression of endothelial alpha globin, a protein predominantly expressed in resistance arteries. Carotids from mice with PAI-1, but lacking alpha globin (Hba1-/-), demonstrated that l-nitro-arginine methyl ester, an inhibitor of nitric oxide signaling, was able to prevent arterial relaxation.

Conclusions: The presence or absence of MEJs is an important determinant for influencing heterocellular communication in the arterial wall. In particular, alpha globin expression, induced within newly formed endothelial cell projections, may influence the balance between endothelial-derived hyperpolarization and nitric oxide-mediated vasodilation.

Keywords: alpha-globins; basement membrane; carotid arteries; endothelial cell; gap junctions; nitric oxide; plasminogen activator inhibitor-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Carotid Arteries / drug effects*
  • Carotid Arteries / physiology
  • Cell Communication / drug effects
  • Cell Communication / physiology*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / physiology
  • Endothelium, Vascular / physiology
  • Enzyme Inhibitors / pharmacology
  • Indoles / pharmacology
  • Intercellular Junctions / drug effects
  • Intercellular Junctions / metabolism
  • Intercellular Junctions / physiology*
  • Male
  • Mice
  • Muscle, Smooth, Vascular / cytology*
  • Myography / methods
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / metabolism
  • Oximes / pharmacology
  • Plasminogen Activator Inhibitor 1 / pharmacology
  • Serine Proteinase Inhibitors / pharmacology
  • Vasodilation / drug effects
  • Vasodilation / physiology*
  • Vasodilator Agents / pharmacology
  • alpha-Globins / metabolism


  • 6,7-dichloro-1H-indole-2,3-dione 3-oxime
  • Enzyme Inhibitors
  • Indoles
  • Oximes
  • Plasminogen Activator Inhibitor 1
  • Serine Proteinase Inhibitors
  • Vasodilator Agents
  • alpha-Globins
  • Nitric Oxide
  • Acetylcholine
  • NG-Nitroarginine Methyl Ester