Key result
Perfusion of 10 µM H2O2 in intact rat venules induced a large magnitude of NO production, leading to caspase activation, endothelial Ca2+ accumulation, cell apoptosis, and an 8-fold increase in microvessel permeability.
Why the study?
Does perfusion of H2O2 increase microvessel permeability and cell apoptosis in individually perfused rat mesenteric venules?
Does perfusion of H2O2 increase microvessel permeability and cell apoptosis in individually perfused rat mesenteric venules?
Absolute Event Rate: 8% vs 1%
p-value: p=<0.01
H2O2 at micromolar concentrations induces a large magnitude of NO in intact venules, causing caspase activation-mediated endothelial Ca2+ accumulation, cell apoptosis, and increases in permeability.
May implicate H2O2-NO signaling in endothelial injury; leaves open human microvascular relevance.
Although elevated levels of H(2)O(2) have been implicated to play important roles in the pathogenesis of various cardiovascular diseases, the underlying mechanisms remain unclear. This study aims to examine the effect of H(2)O(2) on endothelial nitric oxide (NO) production in intact venules, and elucidate the role and mechanisms of NO in H(2)O(2)-induced increases in microvessel permeability. Experiments were conducted on individually perfused rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp), and endothelial [Ca(2+)](i) was measured on fura-2-loaded vessels. Perfusion of H(2)O(2) (10 μM) caused a delayed and progressively increased endothelial [Ca(2+)](i) and Lp, a pattern different from inflammatory mediator-induced immediate and transient response. Under the same experimental conditions, measuring endothelial NO via DAF-2 and the spatial detection of cell apoptosis by fluorescent markers revealed that H(2)O(2) induced two phases of NO production followed by caspase activation, intracellular Ca(2+) accumulation, and vascular cell apoptosis. The initial NO production was correlated with increased endothelial NO synthase (eNOS) Ser(1177) phosphorylation in the absence of elevated endothelial [Ca(2+)](i), whereas the second phase of NO depended on increased [Ca(2+)](i) and was associated with Thr(495) dephosphorylation without increased Ser(1177) phosphorylation. Inhibition of NOS prevented H(2)O(2)-induced caspase activation, cell apoptosis, and increases in endothelial [Ca(2+)](i) and Lp. Our results indicate that H(2)O(2) at micromolar concentration is able to induce a large magnitude of NO in intact venules, causing caspase activation-mediated endothelial Ca(2+) accumulation, cell apoptosis, and increases in permeability. The mechanisms revealed from intact microvessels may contribute to the pathogenesis of oxidant-related cardiovascular diseases.
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Zhou et al. (2012) studied Oxidative stress-induced microvessel permeability. H2O2 vs. Albumin-Ringer solution was evaluated on Hydraulic conductivity (Lp) at 2 hours (p=<0.01). Perfusion of 10 µM H2O2 in intact rat venules induced a large magnitude of NO production, leading to caspase activation, endothelial Ca2+ accumulation, cell apoptosis, and an 8-fold increase in microvessel permeability.
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