Shear Stress Regulates Endothelial Microparticle Release

Abstract

Rationale: Endothelial activation and apoptosis release membrane-shed microparticles (EMP) that emerge as important biological effectors. Objective: Because laminar shear stress (SS) is a major physiological regulator of endothelial survival, we tested the hypothesis that SS regulates EMP release. Methods and Results: EMP levels were quantified by flow cytometry in medium of endothelial cells subjected to low or high SS (2 and 20 dyne/cm 2 ). EMP levels augmented with time in low SS conditions compared with high SS conditions. This effect was sensitive to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Rho kinases inhibitors but unaffected by caspase inhibitors. Low SS-stimulated EMP release was associated with increased endothelial Rho kinases and ERK1/2 activities and cytoskeletal reorganization. Overexpression of constitutively active RhoA stimulated EMP release under high SS. We also examined the effect of nitric oxide (NO) in mediating SS effects. L-NG-nitroarginine methyl ester (L-NAME), but not D-NG-nitroarginine methyl ester, increased high SS-induced EMP levels by 3-fold, whereas the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) decreased it. L-NAME and SNAP did not affect Rho kinases and ERK1/2 activities. Then, we investigated NO effect on membrane remodeling because microparticle release is abolished in ABCA1-deficient cells. ABCA1 expression, which was greater under low SS than under high SS, was augmented by L-NAME under high SS and decreased by SNAP under low SS conditions. Conclusions: Altogether, these results demonstrate that sustained atheroprone low SS stimulates EMP release through activation of Rho kinases and ERK1/2 pathways, whereas atheroprotective high SS limits EMP release in a NO-dependent regulation of ABCA1 expression and of cytoskeletal reorganization. These findings, therefore, identify endothelial SS as a physiological regulator of microparticle release.

The Structural Factor of Hypertension

“…Structural rarefaction may result from a destructive process or be the consequence of insufficient angiogenesis, in response to decreased bioavailability of nitric oxide. 18 For instance, the loss of shear stress in nonperfused microvessels may lead to decreased nitric oxide production, promoting endothelial cell apoptosis and microvascular rarefaction. 18 Capillary rarefaction could represent an early structural abnormality in borderline hypertension and in offspring from hypertensive parents.…”

“…18 For instance, the loss of shear stress in nonperfused microvessels may lead to decreased nitric oxide production, promoting endothelial cell apoptosis and microvascular rarefaction. 18 Capillary rarefaction could represent an early structural abnormality in borderline hypertension and in offspring from hypertensive parents. 17,19 …”

Microvesicles as Cell–Cell Messengers in Cardiovascular Diseases

“…Microparticle release increases under stress conditions, but recent findings indicate that apoptosis is not always a prerequisite. 4,5 During their formation, microparticles retain surface molecules from parent cells, as well as part of their cytosolic content (proteins, RNA, microRNA). The smallest membrane vesicles are exosomes, with a diameter of ≈40 to 100 nm.…”

Cellular Biomarkers of Endothelial Damage Associated With Adverse Prognosis in Acute Coronary Events

“…Многие исследователи считают, что основ-ной функцией ЭАМ является обеспечение меж-клеточных коммуникаций, перенос биологически активных молекул, цитокинов, хемокинов, факто-ров роста, микро-РНК, которые участвуют в ин-формационном обеспечении тканей [8,11,12,24]. Стимуляторами продукции ЭАМ могут быть про-воспалительные цитокины [16,17], ангиотензин-2 [14], оксидативный стресс [13,14], стресс напря-жения-сдвига [14]. Образование микрочастиц, как полагают, происходит путем везикуляции или «блеббинга» клеточной мембраны.…”

“…В ядрах Ca 2+ модулирует транскрипцию генов и нукле-азы, которые контролируют клеточный апоптоз [13]. Стресс напряжения-сдвига также стимулиру-ет высвобождение эндотелиальных микрочастиц через активацию эндотелиальных Rho-киназных и ингибитор протеинкиназ-1 и 2 -зависимых пу-тей [13,14]. Так же стоит отметить, что «блеббинг» плазматической мембраны происходит независимо от других апоптотических изменений и не участву-ет в распознавании и захвате апоптотических кле-ток макрофагами [15].…”