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Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKC[beta] inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKC[beta]1 and -[beta]2, but not PKC[alpha], -[delta], or -[zeta], decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKC[beta]1 and -[beta]2, but not PKC[alpha] or -[delta], also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKC[beta]2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKC[beta] in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance., The development of atherosclerosis is preceded by, and partly results from, decreased production of endothelium-derived nitric oxide (NO) (1). Insulin resistance, an independent risk factor for cardiovascular disease (2), is [...]