Shear-Induced Nitric Oxide Production by Endothelial Cells

Abstract

We present a biochemical model of the wall shear stress-induced activation of endothelial nitric oxide synthase (eNOS) in an endothelial cell. The model includes three key mechanotransducers: mechanosensing ion channels, integrins, and G protein-coupled receptors. The reaction cascade consists of two interconnected parts. The first is rapid activation of calcium, which results in formation of calcium-calmodulin complexes, followed by recruitment of eNOS from caveolae. The second is phosphorylation of eNOS by protein kinases PKC and AKT. The model also includes a negative feedback loop due to inhibition of calcium influx into the cell by cyclic guanosine monophosphate (cGMP). In this feedback, increased nitric oxide (NO) levels cause an increase in cGMP levels, so that cGMP inhibition of calcium influx can limit NO production. The model was used to predict the dynamics of NO production by an endothelial cell subjected to a step increase of wall shear stress from zero to a finite physiologically relevant value. Among several experimentally observed features, the model predicts a highly nonlinear, biphasic transient behavior of eNOS activation and NO production: a rapid initial activation due to the very rapid influx of calcium into the cytosol (occurring within 1-5 min) is followed by a sustained period of activation due to protein kinases.

Inwardly rectifying K+ channels are major contributors to flow‐induced vasodilatation in resistance arteries

“…An earlier study showed shear stress may activate Kir channels in a cell-attached mode though the channels in the pipette are not exposed to shear directly, suggesting that shear stress can activate these channels indirectly (Jacobs et al 1995). Possible upstream mechanosensors include but are not limited to integrins, glycocalyx, other ion channels, and G proteins (Ando & Yamamoto, 2009;Sriram et al 2016). Mechanosensitive ion channels, specifically those permeable to Ca 2+ , are believed to be a major source of entry for Ca 2+ into ECs upon exposure to shear stress (Wiesner et al 1997); however, any existing link between mechanosensitive Ca 2+ channel activation and subsequent Kir channel activation has yet to be investigated.…”

“…Mechanosensitive ion channels, specifically those permeable to Ca 2+ , are believed to be a major source of entry for Ca 2+ into ECs upon exposure to shear stress (Wiesner et al 1997); however, any existing link between mechanosensitive Ca 2+ channel activation and subsequent Kir channel activation has yet to be investigated. Shear also activates endothelial GPCRs and integrins that converge onto PIP 2 to promote IP 3 and PIP 3 formation, respectively (Chachisvilis et al 2006;Loufrani et al 2008;Sriram et al 2016), but a decrease in PIP 2 availability would be expected to deactivate rather than activate Kir channels. Another open question is whether an increase in Kir current is the result of an increase in the open probability of the channels, activation of previously dormant channels or insertion of new channels into the plasma membrane.…”

Increased endothelial shear stress improves insulin‐stimulated vasodilatation in skeletal muscle

“…However, it remains unknown if increased shear stress, in the absence of muscle contraction, augments the vasodilator actions of insulin. Given that both shear stress and insulin activate eNOS through PI3K signalling pathways (Eringa et al 2002(Eringa et al , 2007Kim et al 2006;Sriram et al 2016), it is plausible that shear stress renders the vasculature more insulin-responsive. To test this hypothesis, complementary experiments were conducted using (i) cultured endothelial cells, (ii) isolated and pressurized skeletal muscle arterioles from swine, and (iii) humans.…”

NO-Releasing Nanoparticles Ameliorate Detrusor Overactivity in Transgenic Sickle Cell Mice via Restored NO/ROCK Signaling

“…This effect of NO-np treatment was associated with a reversal of downregulated Akt/eNOS activities, and reversal of upregulated ROCK activity, in the SCD mouse bladder. We propose that increased local NO by NO-np treatment resulted in enhanced blood flow and shear forces on the urothelium, activated Akt/eNOS (Ser-1177) phosphorylation cascade, and promoted NO release and relaxation of the bladder (Dimmeler S et al, 1999;Sriram K et al, 2016;Hurt KJ et al, 2002). Increased NO may further downregulate the contractile ROCK pathway activity in the bladder, further improving bladder relaxation (Fig.…”