Dysregulation of Extracellular Adenosine Levels by Vascular Smooth Muscle Cells From Spontaneously Hypertensive Rats

Abstract

Abstract-The objective of this investigation was to determine whether the regulation of extracellular adenosine levels by smooth muscle cells (SMCs) from conduit arteries (aorta) and resistance microvessels (renal arterioles) is different in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto (WKY) rats. Basal extracellular adenosine levels were decreased in cultured aortic and arteriolar SHR SMCs, and the increase in extracellular adenosine levels induced by stimulation of the cAMP-adenosine pathway was less in aortic and arteriolar SHR SMCs. Extracellular adenosine levels were lower in SHR SMCs, however, even when the cAMP-adenosine pathway was inhibited with 3-isobutyl-1-methylxanthine. Inhibition of adenosine kinase with iodotubercidin and inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl) adenine increased extracellular adenosine; however, only inhibition of adenosine deaminase equalized extracellular adenosine levels in SHR versus WKY SMCs. Membrane-disrupted SHR SMCs metabolized exogenous adenosine faster than WKY SMCs did, and this difference was abolished by inhibition of adenosine deaminase but not adenosine kinase. SHR SMCs demonstrated a greater proliferative response than WKY SMCs. This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase-resistant adenosine analogue). We conclude that dysregulation of extracellular adenosine levels exists in SHR SMCs, that this dysregulation is not due to a defect in the cAMP-adenosine pathway but rather to enhanced activity of adenosine deaminase, and that the dysregulation of extracellular adenosine mediates the enhanced proliferative response of SHR SMCs. Key Words: adenosine deaminase Ⅲ adenosine kinase Ⅲ hypertension Ⅲ proliferation Ⅲ vascular disease S mooth muscle cells (SMCs) within conduit and resistance arteries are importantly involved in the pathophysiology of vascular remodeling induced by hypertension. 1 In this regard, SMC growth, both hypertrophic 1 and hyperplastic, 2,3 contributes to pathological structural changes within the vessel wall in spontaneously hypertensive rats (SHR). SMC growth is regulated by multiple factors. 1 Under normal conditions, vascular SMC quiescence is maintained by a balance between vessel wall-derived and circulating growth inhibitors and growth promoters. 1 Disruption of the balanced generation of growth promoters and growth inhibitors under pathological conditions triggers a cascade of events leading to increased proliferation of SMCs and enhanced deposition of extracellular matrix proteins by SMCs. Therefore, endogenous factors that are generated by cells within the vessel wall and that inhibit SMC growth may play a major vasoprotective role, and decreased vascular levels of growth-inhibitory factors may contribute to vascular disease in hypertension.In this regard, it is conceivable that dysregulation of vascular adenosine levels in hyp...

Upregulation of inducible NO synthase by exogenous adenosine in vascular smooth muscle cells activated by inflammatory stimuli in experimental diabetes

“…With regard to major purine-inactivating pathways, ADA and CD73 were remarkably active in both control and diabetic VSMCs, with no residual AMP or adenosine found in the medium 24 h after supplementation. We also found a tendency to increased inosine generation following adenosine supplementation by diabetic VSMCs, possibly as a result of increased ADA activity, as described in diabetic patients [ 43 ] and in experimental models of hypertension [ 44 ]. Residual inosine concentrations following inosine supplementation to diabetic VSMCs were also higher than in control VSMCs.…”

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…For example, hypertrophic myocardium is intolerant of ischemic and other forms of insult, likely for multiple reasons. Not only is adenosine potentially involved in regulating cardiac and vascular hypertrophic growth (66)(67)(68)(69), but also adenosinergic signaling is modified in hypertrophic tissue (204,273,307). Whether such changes contribute to the intolerant phenotypes remains to be directly tested.…”

“…Whether such changes contribute to the intolerant phenotypes remains to be directly tested. However, adenosinergic therapy has been shown to counter detrimental phenotypic changes associated with hypertrophy (39), dysregulation of adenosine formation may occur in hypertrophy (53), and dysregulation of adenosine formation with hypertension is involved in modifying vascular proliferation (69). There is therefore good evidence that cardiovascular responses to these disease states are associated with altered adenosine signaling and/or protection.…”

Adenosine Inhibits PDGF-Induced Growth of Human Glomerular Mesangial Cells Via A 2B Receptors

“…5 Adenosine is a potent regulator of growth in both vascular and nonvascular cells. 6 -8 We have previously shown that adenosine inhibits growth of renal arteriolar 9 and aortic smooth muscle 6 cells, which play a key role in vascular remodeling leading to vaso-occlusive disorders. Moreover, using receptor-specific agonists and antagonists as well as antisense oligonucleotides, we demonstrated that the antimitogenic effects of adenosine are mediated by activation of A 2B receptors.…”