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Abstract no.: 6
Endothelium‐dependent relaxation by purinergic receptors in the aorta of apolipoprotein E‐deficient mice
Author(s) -
Korda A.,
Guns P.J.D.,
Crauwels H.M.,
Hove C.E.,
Holvoet P.,
Bult H.
Publication year - 2005
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2004.00286_6.x
Subject(s) - purinergic receptor , apolipoprotein e , medicine , endocrinology , endothelium , receptor , phenylephrine , aorta , apolipoprotein b , thoracic aorta , chemistry , biology , cholesterol , blood pressure , disease
Previously we reported that the acetylcholine‐induced relaxation in the isolated aorta of apolipoprotein E‐deficient (apoE ‐/‐ ) mice deteriorates after the development of atherosclerotic plaques, but remains normal in adjacent, plaque‐free segments. The present study investigated the presence of functional purinergic receptors in the murine aorta, and whether their function changes before or after the development of atherosclerosis. Endothelium‐dependent relaxation was measured in aorta segments of apoE ‐/‐ , C57BL6 (WT) and human apoAI‐overexpressing apoE ‐/‐ mice (apoAI/apoE ‐/‐ ) on regular chow. Rings were isometrically contracted with phenylephrine to 50% of their maximum force before performing cumulative concentration‐response curves to different nucleotides or their stable analogues. After the functional study, the cross‐sectional area of the plaque was determined in every segment. The nucleotides induced complete (UTP, UDP, ATP) or partial (ADP) relaxation that was abolished by endothelial cell removal or nitric oxide (NO) synthase inhibition. The responses pointed to the presence of functional P2y1, P2y2 or P2y4 receptors on endothelial cells. RT‐PCR confirmed the presence of P2y1 and P2y4 mRNA in the aorta of WT mice. Nucleotide responses were unaltered in lesion‐free apoE ‐/‐ mice (5 months). However, in atherosclerotic segments of apoE ‐/‐ mice (18 months), the relaxation to ATP was impaired compared to age‐matched WT controls (maximum amplitude (E max ) 25 ± 14%, n = 6 vs. 90 ± 3%, n = 5, P < 0.01). A similar defect was seen for the stable analogue ATP‐gamma‐S (E max 36 ± 12% vs. 86 ± 3%, P < 0.01). Atherosclerotic apoE ‐/‐ segments were less sensitive to the NO donor spermineNONOate (pD 2 6.74 ± 0.18) than WT segments (7.25 ± 0.20), but maximum relaxation was unaltered. In non‐atherosclerotic aorta segments of the same apoE ‐/‐ mice all relaxation responses remained normal and were not different from WT. Strong negative correlations ( P < 0.001) existed between lesion size and the E max for ATP (r s = −0.82) and ATP‐gamma‐S (r s = −0.73) in apoE ‐/‐ mice. ApoAI overexpression improved the purinergic responses (E max ATP 64 ± 9%, ATP‐gamma‐S 64 ± 10%, n = 5) and these were not different from WT ( P > 0.05). An analysis of covariance with plaque size as covariate suggested that this benefit was secondary to the strongly reduced plaque formation in apoAI/apoE ‐/‐ mice. It is concluded that functional P2 y receptors are present on murine aortic endothelium. Furthermore, endothelium‐dependent purinergic relaxation declines after plaque development. This deterioration involves decreased bioavailability of NO rather than enhanced ATP degradation. The defect is, however, not systemic since the responses remain unaltered in plaque‐free segments of atherosclerosis‐prone apoE ‐/‐ mice.