Adventitia-derived hydrogen peroxide impairs relaxation of the rat carotid artery via smooth muscle cell p38 mitogen-activated protein kinase.
The role of adventitia-derived reactive oxygen species (ROS) in vascular disease and impaired vascular relaxation is not clear. Based on robust adventitial ROS generation and effects on MAPK involvement in vascular dysfunction, we hypothesized that adventitia-derived ROS hydrogen peroxide (H(2)O(2)) impairs vascular relaxation through activation of medial smooth muscle p38 MAPK. By using a novel in vivo model, the adventitial surface of rat carotid arteries was bathed in situ for 90 min with vehicle, angiotensin II (AngII; 500 nM), AngII+H(2)O(2)-scavenger catalase (3,000 U/ml), AngII+p38 MAPK inhibitor SB203580 (10 μM), or AngII+superoxide dismutase (SOD; 150 U/ml). After these in vivo treatments, ex vivo tone measurements on isolated vessels revealed that periadventitial application of AngII impaired both acetylcholine-induced (endothelium-dependent) and sodium nitroprusside-induced (endothelium-independent) relaxations. In vivo coincubation with catalase or SB203580 significantly improved, but SOD exacerbated AngII-induced impairment of in vitro endothelium-dependent and -independent vascular relaxations. Western blots of vascular media, separated from the adventitia, demonstrated increased medial p38 MAPK activation and decreased medial phosphatase SHP-2 activity in AngII-treated vessels. These effects were reversed by in vivo periadventitial addition of catalase. These findings provide the first evidence that adventitia-derived H(2)O(2) participates in vascular dysfunction through p38 MAPK activation and SHP-2 inhibition.
Hypertension and Vascular Research Division, Henry Ford Health System, Detroit, MI, USA.
Thomas
T
Cascino
Gabor
G
Csanyi
Imad
I
Al Ghouleh
Augusto C
AC
Montezano
Rhian M
RM
Touyz
Mounir J
MJ
Haurani
Patrick J
PJ
Pagano
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000502:physiology; D002374:Catalase / Q000494:pharmacology; D003238:Connective Tissue / Q000378:metabolism*; D004195:Disease Models, Animal; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D009213:Myography / Q000379:methods; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D007093:Imidazoles; D011725:Pyridines; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C093642:SB 203580