Coordinated Adenine Nucleotide Phosphohydrolysis and Nucleoside Signaling in Posthypoxic Endothelium

Abstract

Limited oxygen delivery to tissues (hypoxia) is common in a variety of disease states. A number of parallels exist between hypoxia and acute inflammation, including the observation that both influence vascular permeability. As such, we compared the functional influence of activated polymorphonuclear leukocytes (PMN) on normoxic and posthypoxic endothelial cells. Initial studies indicated that activated PMN preferentially promote endothelial barrier function in posthypoxic endothelial cells ( Ͼ 60% increase over normoxia). Extension of these findings identified at least one soluble mediator as extracellular adenosine triphosphate (ATP). Subsequent studies revealed that ATP is coordinately hydrolyzed to adenosine at the endothelial cell surface by hypoxia-induced CD39 and CD73 ( Ͼ 20-and Ͼ 12-fold increase in mRNA, respectively). Studies in vitro and in cd39 -null mice identified these surface ecto-enzymes as critical control points for posthypoxia-associated protection of vascular permeability. Furthermore, insight gained through microarray analysis revealed that the adenosine A 2B receptor (AdoRA 2B ) is selectively up-regulated by hypoxia ( Ͼ 5-fold increase in mRNA), and that AdoRA 2B antagonists effectively neutralize ATP-mediated changes in posthypoxic endothelial permeability. Taken together, these results demonstrate transcription coordination of adenine nucleotide and nucleoside signaling at the vascular interface during hypoxia.

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…The transcription factor hypoxia inducible factor (HIF) is also overexpressed in renal hypoxia and is in part responsible for the increased expression of A 2B R in this setting [54]. Another transcription factor, cAMP receptor binding protein (CREB), also increases A 2B R expression [55,56]. As discussed above, the A 2B R is a G s -coupled protein receptor, which activates adenylyl cyclase and increases cAMP production; thus, this serves as a positive feedback mechanism wherein A 2B R increases its own expression and promotes renal fibrosis in the setting of hypoxia.…”

Hypoxia and gastrointestinal disease

“…A number of studies have revealed that HIF elicits a barrier protective program in the intestine [17][18][19][20]. While originally guided by microarray analysis of differentially expressed messenger ribonucleic acid (mRNA) in cultured epithelial cells subjected to hypoxia, these studies have proven robust in a number of animal models of inflammation.…”

“…Third, HIF-dependent epithelial barrier-protective pathways driven by hypoxia tend to be more "nonclassical" regulators of barrier function. Rather than classic junctional proteins such as occludin or claudin(s), hypoxia-induced enhancement of barrier function occurs through diverse pathways, ranging from increased mucin production [21] and molecules that modify mucins (e.g., intestinal trefoil factor) [17], to xenobiotic clearance (P-glycoprotein) [18] to nucleotide metabolism (ecto-5′-nucleotidase, CD73) [19][20] and nucleotide signaling (adenosine A2B receptor) [20] (Fig. 2).…”

Overexpression of NTPDase2 in gliomas promotes systemic inflammation and pulmonary injury

“…Although the presence of ectonucleotidases is critical for maintaining the vascular homeostasis, little is known about its expression regulation at the molecular level. Modulated expression of NTPDase1 and ecto-5′-NT/CD73 has been closely associated with inflammatory cytokines, oxidative stress, and hypoxia [46][47][48][49]. Therefore, the pro-inflammatory environment present in C6NT2 glioma-implanted rats may modulate the ectonucleotidase expression in platelets.…”