Extracellular adenosine enhances pulmonary artery vasa vasorum endothelial cell barrier function via Gi/ELMO1/Rac1/PKA-dependent signaling mechanisms

Am J Physiol Cell Physiol. 2020 Jul 1;319(1):C183-C193. doi: 10.1152/ajpcell.00505.2019. Epub 2020 May 20.


The vasa vasorum (VV), the microvascular network around large vessels, has been recognized as an important contributor to the pathological vascular remodeling in cardiovascular diseases. In bovine and rat models of hypoxic pulmonary hypertension (PH), we have previously shown that chronic hypoxia profoundly increased pulmonary artery (PA) VV permeability, associated with infiltration of inflammatory and progenitor cells in the arterial wall, perivascular inflammation, and structural vascular remodeling. Extracellular adenosine was shown to exhibit a barrier-protective effect on VV endothelial cells (VVEC) via cAMP-independent mechanisms, which involved adenosine A1 receptor-mediated activation of Gi-phosphoinositide 3-kinase-Akt pathway and actin cytoskeleton remodeling. Using VVEC isolated from the adventitia of calf PA, in this study we investigated in more detail the mechanisms linking Gi activation to downstream barrier protection pathways. Using a small-interference RNA (siRNA) technique and transendothelial electrical resistance assay, we found that the adaptor protein, engulfment and cell motility 1 (ELMO1), the tyrosine phosphatase Src homology region 2 domain-containing phosphatase-2, and atypical Gi- and Rac1-mediated protein kinase A activation are implicated in VVEC barrier enhancement. In contrast, the actin-interacting GTP-binding protein, girdin, and the p21-activated kinase 1 downstream target, LIM kinase, are not involved in this response. In addition, adenosine-dependent cytoskeletal rearrangement involves activation of cofilin and inactivation of ezrin-radixin-moesin regulatory cytoskeletal proteins, consistent with a barrier-protective mechanism. Collectively, our data indicate that targeting adenosine receptors and downstream barrier-protective pathways in VVEC may have a potential translational significance in developing pharmacological approach for the VV barrier protection in PH.

Keywords: Gi; Rac1; adenosine; endothelial barrier; vasa vasorum.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenosine / metabolism*
  • Adenosine / pharmacology
  • Animals
  • Cattle
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Male
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Vasa Vasorum / drug effects
  • Vasa Vasorum / metabolism*
  • rac1 GTP-Binding Protein / metabolism*


  • Adaptor Proteins, Signal Transducing
  • ELMO1 protein, mouse
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • rac1 GTP-Binding Protein
  • Adenosine