Endothelial nitric-oxide synthase (eNOS) generates the key signaling molecule nitric oxide in response to intralumenal hormonal and mechanical stimuli We designed studies to determine whether eNOS is localized to plasmalemmal microdomains implicated in signal transduction called caveolae Using immunoblot analysis, eNOS protein was detected in caveolar membrane fractions isolated from endothelial cell plasma membranes by a newly developed detergent-free method; eNOS protein was not found in noneaveolar plasma membrane Similarly, NOS enzymatic activity was 94-fold enriched in caveolar membrane versus whole plasma membrane, whereas it was undetectable in non-caveolar plasma membrane 51-86% of total NOS activity in postnuclear supernatant was recovered in plasma membrane, and 57-100% of activity in plasma membrane was recovered in caveolae Immunoelectron microscopy showed that eNOS heavily decorated endothelial caveolae, whereas coated pits and smooth plasma membrane were devoid of gold particles Furthermore, eNOS was targeted to caveolae in COS-7 cells transfected with wild-type eNOS cDNA Studies with eNOS mutants revealed that both myristoylation and palmitoylation are required to target the enzyme to caveolae and that each acylation process enhances targeting by 10-fold Thus, acylation targets eNOS to plasmalemmal caveolae Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide

Acylation targets endothelial nitric oxide synthase to plasmalemmal caveolae

Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.

/pdf/diabetic-microvascular-disease-an-endocrine-society-15g2pqnt39.pdf

Diabetic Microvascular Disease: An Endocrine Society Scientific Statement.

Role of reactive oxygen and nitrogen species in the vascular responses to inflammation

Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO has also been implicated in diseases that are related to neurotransmission and cancer although it is likely that these processes involve NO at higher concentrations and from nonvascular cell sources. Conversely, NO and drugs that directly or indirectly increase NO signaling have found clinical applications in both age-related diseases and in younger individuals. This focused review considers recently reported advances being made in the field of NO signaling regulation at several levels including enzymatic production, receptor function, interacting partners, localization of signaling, matrix-cellular and cell-to-cell cross talk, as well as the possible impact these newly described mechanisms have on health and disease.

/pdf/nitric-oxide-what-s-new-to-no-31t6i4ym08.pdf

Nitric oxide: what’s new to NO?

iNOS as a metabolic enzyme under stress conditions.

Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors.

Kinins are vasoactive peptides that play important roles in cardiovascular homeostasis, pain and inflammation. After release from their precursor kininogens, kinins or their C-terminal des-Arg metabolites activate two distinct G protein-coupled receptors (GPCR), called B2 (B2R) or B1 (B1R). The B2R is expressed constitutively with a wide tissue distribution. In contrast, the B1R is not expressed under normal conditions but is upregulated by tissue insult or inflammatory mediators. The B2R is considered to mediate many of the acute effects of kinins while the B1R is more responsible for chronic responses in inflammation. Both receptors can couple to Gai and Gaq families of G proteins to release mediators such as nitric oxide (NO), arachidonic acid, prostaglandins, leukotrienes and endothelium-derived hyperpolarizing factor and can induce the release of other inflammatory agents. The focus of this review is on the different transduction events that take place upon B2R and B1R activation in human endothelial cells that leads to generation of NO via activation of different NOS isoforms. Importantly, B2R-mediated eNOS activation leads to a transient (5 min) output of NO in control endothelial cells whereas in cytokine-treated endothelial cells, B1R activation leads to very high and prolonged (90 min) NO production that is mediated by a novel signal transduction pathway leading to post-translational activation of iNOS.

Special Issue on Peptide Receptors: Focus on Neuropeptides and Kinins Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors

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Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors.

Special Issue on Peptide Receptors: Focus on Neuropeptides and Kinins Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors