Cellular Mechanisms for the Effects of Nitric Oxide on the Blood Brain Barrier

There are several potential mechanisms by which nitric oxide could contribute to changes in permeability of the blood-brain barrier (Figure 2). It appears that changes in permeability of the blood-brain barrier during stimulation with inflammatory mediators, for example, may involve the activation of the cGMP pathway by nitric oxide. Activation of this pathway may, in turn, activate a cascade of cellular pathways, including protein kinase G, protein kinase C, and/or mitogen activated protein kinase (MAPK). In addition, it is possible that the synthesis/release of nitric oxide may stimulate the contraction of endothelial cytoskeletal proteins to produce contraction of adjacent endothelial cells,

Ca2+

Figure 2 Schematic representation of potential pathways by which nitric oxide (NO) may influence the permeability of the blood-brain barrier. It appears that an agonist (A) binding to a receptor may activate phospholi-pase C (PLC) via a G protein (Gp) to catalyze the production of inositol trisphosphate (IP3) and diacylglycerol (DAG) from inositol bisphosphate (PIP2). IP3 stimulates the release of calcium from the endoplasmic reticulum (ER) and also increases the influx of extracellular calcium, leading to activation of nitric oxide synthase (NOS) to produce NO from L-arginine. NO appears to stimulate guanylate cyclase (GC) to produce cyclic GMP (cGMP), a potent activator of protein kinase G (PKG). PKG may directly increase the permeability of the blood-brain barrier, may interact with protein kinase C (PKC), and/or may stimulate mitogen activated protein kinase (MAPK) to produce an increase in permeability of the blood-brain barrier. In parallel, DAG may stimulate PKC, may interact with PKG, and/or may stimulate MAPK to produce an increase in permeability of the blood-brain barrier. In addition to this pathway, NO may have direct effects on the formation of pinocytotic vesicles within endothelial cells and/or on tight junctional proteins to produce a pathway for the movement of molecules from the vasculature into brain tissue. Further, changes in permeability of the blood-brain barrier may be related to the effects of NO on endothelial cytoskeletal components. Thus, an increase in intracellular calcium via a Ca-calmodulin interaction (CaM) activates myosin light chain kinase (MLCK) to phosphorylate myosin light chain (MLC), leading to an increase in actinomyosin interaction, and subsequent endothelial cell contraction to increase permeability of the blood-brain barrier. It is also possible that an agonist and/or NO may stimulate myosin light chain phos-phorylation (MLC-P) through Rho kinase (Rho-K) pathway inhibition of myosin light chain phosphatase (MLCP) activity resulting in contraction of actinomyosin filaments and an increase in permeability of the blood-brain barrier.

and thus provide a pathway for the movement of molecules and/or influence the formation of pinocytotic vesicles within cerebral endothelium (Figure 2). Further, it is possible that that nitric oxide does not directly produce an increase in vascular permeability, but plays an obligatory role in macro-molecular transport, as has been shown for peripheral blood vessels. Future directions to determine the precise role of nitric oxide and mechanisms by which nitric oxide produces changes in permeability of the blood-brain barrier in response to various stimuli, including inflammatory mediators and mechanical and metabolic stimuli, will certainly advance our understanding of this process and will contribute to new therapeutic approaches for the treatment of inflammatory cerebrovascular diseases.

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Essentials of Human Physiology

Essentials of Human Physiology

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