Abstract-Angiotensin II induces endothelial dysfunction by reducing NO availability and increasing reactive oxygen species. We assessed whether cyclooxygenase (COX)-1 or COX-2 participate in the angiotensin II-induced endothelial dysfunction in murine mesenteric small arteries and examined the role of reduced nicotinamide-adenine dinucleotide phosphate-dependent reactive oxygen species production. Mice received angiotensin II (600 ng/kg per minute, SC), saline (controls), angiotensin II ϩ apocynin (reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, 2.5 mg/day), or apocynin alone for 2 weeks. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In controls, acetylcholine-induced relaxation was inhibited by N G -monomethyl-L-arginine and unaffected by DFU (COX-2 inhibitor), SC-560 (COX-1 inhibitor), or ascorbic acid. In angiotensin II-infused animals, the attenuated response to acetylcholine was less sensitive to N G -monomethyl-L-arginine, unaffected by DFU, and enhanced by SC-560 and, similarly, by SQ-29548, a thromboxane-prostanoid receptor antagonist. Moreover, response to acetylcholine was unchanged by ozagrel, a thromboxane synthase inhibitor, and normalized by ascorbic acid. Apocynin prevented the angiotensin II-induced vascular dysfunctions. In angiotensin II-infused mice, RT-PCR analysis showed a significant COX-2 downregulation, whereas COX-1 expression was upregulated. These changes were unaffected by apocynin. Modulation of COX isoform by angiotensin II was also documented by immunohistochemistry. In small mesenteric vessels, the reduced NO availability and oxidant excess, which characterize endothelial dysfunction secondary to angiotensin II, are associated with a reduced COX-2 and an increased COX-1 function and expression. Angiotensin II causes an oxidative stress-independent COX-1 overexpression, whereas angiotensin II-mediated oxidant excess production stimulates COX-1 activity to produce a contracting prostanoid endowed with agonist activity on thromboxane-prostanoid receptors. Key Words: angiotensin II Ⅲ microcirculation, cyclooxygenase Ⅲ endothelium Ⅲ oxidative stress I t is widely accepted that angiotensin (Ang) II is greatly implicated in the development of endothelial dysfunction in small resistance arteries, 1,2 mainly through an increased generation of reactive oxygen species (ROS) via vascular reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase activation. [3][4][5][6] Mesenteric arteries from Ang II-infused mice are characterized by a blunted endothelium-dependent relaxation, as a consequence of a reduced NO availability because of oxidant excess. 5 Recent evidence indicates that another pathway involved in endothelial dysfunction is cyclooxygenase (COX) activity. Thus, prostaglandins (PGs) have been shown to play a major role in modulating vascular tone, and COX represents a key enzyme in PG synthesis. Indeed, COX metabolizes arachidonic acid into the unstable intermediate PGH 2 , which, in turn, is converted by an array...