Purinergic Signaling and Blood Vessels in Health and Disease

Hollmén

et al. 2016

Purinergic Signalling

Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5′-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.

Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Regulation of CD73 in the development of lower limb atherosclerosis

Hollmén

et al. 2016

Purinergic Signalling

“…In addition, functional A 2A AR is reported to be expressed on both EC and SMC [9], which is in agreement with our previous data showing positive A 2A AR staining in both cell types of isolated mouse coronary arteries [40]. Therefore, it is reasonable to speculate that adenosine may act through A 2A AR in both cell types producing H 2 O 2 , and activation of A 2A AR-H 2 O 2 pathway may result in different downstream vasodilator mechanisms, as activation of A 2A AR in different cell types of coronary artery stimulates either cAMP-PKA or cGMP-PKG signaling [9,12,58,59]. On the other hand, the cross talk of these vasodilator mechanisms exists.…”

Section: Adenosine-induced Increase In Coronary Flow Is Mediated In Pmentioning

confidence: 87%

“…This discrepancy may be due to different animal models, differences in species, and/or different agonists and antagonists used in these studies. It is well established that the coronary effects of adenosine are mediated through the activation of its four subtypes of receptors, namely A 1 , A 2A , A 2B , and A 3 receptors (ARs) [9,12,13]. The role of these receptors has been studied in various species [12].…”

Section: Introductionmentioning

confidence: 99%

“…It is well established that the coronary effects of adenosine are mediated through the activation of its four subtypes of receptors, namely A 1 , A 2A , A 2B , and A 3 receptors (ARs) [9,12,13]. The role of these receptors has been studied in various species [12]. With an overall coronary vasodilation, A 2A AR predominantly and A 2B AR minimally contribute to dilating coronary vasculature [14][15][16], whereas A 1 AR and A 3 AR counteract the effects of A 2A /A 2B ARs resulting in a diminished coronary vasodilation [15,17,18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Zhou

Rajamani

Labazi

et al. 2015

Purinergic Signalling

Adenosine increases coronary flow mainly through the activation of A 2A and A 2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A 1 or A 3 ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A 2A but not A 2B ARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H 2 O 2 ) production was measured in isolated coronary arteries from WT, A 2A AR k n o c k o u t ( K O ) , a n d A 2 B A R K O m i c e u s i n g dichlorofluorescein immunofluorescence. Adenosineinduced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A 2B but not A 2A AR KO isolated hearts. Similarly, the A 2A AR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A 2B AR KO, while the A 2B AR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10 μM) increase in H 2 O 2 formation in both WT and A 2B AR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H 2 O 2 production in A 2A AR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H 2 O 2 , which critically depends upon the presence of A 2A AR.

Biology of purinergic signalling: Its ancient evolutionary roots, its omnipresence and its multiple functional significance

2014

Self Cite

The purinergic signalling system, which utilises ATP, related nucleotides and adenosine as transmitter molecules, appeared very early in evolution: release mechanisms and ATP-degrading enzymes are operative in bacteria, and the first specific receptors are present in single cell eukaryotic protozoa and algae. Further evolution of the purinergic signalling system resulted in the development of multiple classes of purinoceptors, several pathways for release of nucleotides and adenosine, and a system of ectonucleotidases controlling extracellular levels of purinergic transmitters. The purinergic signalling system is expressed in virtually all types of tissues and cells, where it mediates numerous physiological reactions and contributes to pathological responses in a variety of diseases.