Increased circulating microparticles in streptozotocin‐induced diabetes propagate inflammation contributing to microvascular dysfunction

Abstract

Key points Circulating microparticles (MPs) are elevated in many cardiovascular diseases and have been considered as biomarkers of disease prognosis; however, current knowledge of MP functions has been mainly derived from in vitro studies and their precise impact on vascular inflammation and disease progression remains obscure. Using a diabetic rat model, we identified a >130‐fold increase in MPs in plasma of diabetic rats compared to normal rats, the majority of which circulated as aggregates, expressing multiple cell markers and largely externalized phosphatidylserine; vascular images illustrate MP biogenesis and their manifestations in microvessels of diabetic rats. Using combined single microvessel perfusion and systemic cross‐transfusion approaches, we delineated how diabetic MPs propagate inflammation in the vasculature and transform normal microvessels into an inflammatory phenotype observed in the microvessels of diabetic rats. Our observations derived from animal studies resembling conditions in diabetic patients, providing a mechanistic insight into MP‐mediated pathogenesis of diabetes‐associated multi‐organ microvascular dysfunction. Abstract In various cardiovascular diseases, microparticles (MPs), the membrane‐derived vesicles released during cell activation, are markedly increased in the circulation. These MPs have been recognized to play diverse roles in the regulation of cellular functions. However, current knowledge of MP function has been largely derived from in vitro studies. The precise impact of disease‐induced MPs on vascular inflammation and disease progression remains obscure. In this study we investigated the biogenesis, profile and functional roles of circulating MPs using a streptozotocin‐induced diabetic rat model with well‐characterized microvascular functions. Our study revealed a >130‐fold increase in MPs in the plasma of diabetic rats compared to normal rats. The majority of these MPs originate from platelets, leukocytes and endothelial cells (ECs), and circulate as aggregates. Diabetic MPs show greater externalized phosphatidylserine (PS) than normal MPs. When diabetic plasma or isolated diabetic MPs were perfused into normal microvessels or systemically transfused into normal rats, MPs immediately adhered to endothelium and subsequently mediated leukocyte adhesion. These microvessels then exhibited augmented permeability responses to inflammatory mediators, replicating the microvascular manifestations observed in diabetic rats. These effects were abrogated when MPs were removed from diabetic plasma or when diabetic MPs were pre‐coated with a lipid‐binding protein, annexin V, suggesting externalized PS to be key in mediating MP interactions with endothelium and leukocytes. Our study demonstrated that the elevated MPs in diabetic plasma are actively involved in the propagation of vascular inflammation through their adhesive surfaces, providing mechanistic insight into the pathogenesis of multi‐organ vascular dysfunction that commonly occurs in diabetic patients.

Production and internalization of extracellular vesicules in normal and under conditions of hyperglycemia and insulin resistance

“…Соответственно, в условиях гипергликемии и инсулинорезистентности эндотелиальная дисфункция формируется быстро и определяет тяжесть других осложнений СД2. На модели стрептозотоцитового диабета крыс было выявлено многократное увеличение эндогенных микрочастиц размером от 220 нм до 1300 нм (разновидность ВВ) у диабетических крыс по сравнению с контролем с гиперэкспрессией поверхностного фосфатидилсерина [36]. Диабетические микрочастицы, находясь в циркуляции, формировали агрегаты и обуславливали повышенную адгезию лейкоцитов и повышенную чувствительность эндотелиоцитов к воспалительным стимулам [36].…”

“…На модели стрептозотоцитового диабета крыс было выявлено многократное увеличение эндогенных микрочастиц размером от 220 нм до 1300 нм (разновидность ВВ) у диабетических крыс по сравнению с контролем с гиперэкспрессией поверхностного фосфатидилсерина [36]. Диабетические микрочастицы, находясь в циркуляции, формировали агрегаты и обуславливали повышенную адгезию лейкоцитов и повышенную чувствительность эндотелиоцитов к воспалительным стимулам [36]. Аналогичные данные получены и в экспериментах моделирования инсулинорезистентности in vitro [37].…”

Interplay between Endoplasmic Reticulum Stress and Large Extracellular Vesicles (Microparticles) in Endothelial Cell Dysfunction

“…Correlation and regression analysis indicated significant positive correlation between endothelial lEVs and HbA1c level, and that endothelial lEVs are independent predictors of endothelial dysfunction (reduced flow-mediated dilation of brachial artery and elevated brachial ankle pulse wave velocity) in diabetic patients, respectively [ 87 ]. Feng et al [ 88 ] and Ishida et al [ 89 ] showed significantly elevated levels of circulating lEVs from endothelial, leukocyte and platelet origins in STZ-induced diabetic rats, compared to non-diabetic rats [ 88 , 89 ].…”

Endoplasmic Reticulum (ER) Stress-Generated Extracellular Vesicles (Microparticles) Self-Perpetuate ER Stress and Mediate Endothelial Cell Dysfunction Independently of Cell Survival

“…Furthermore, a significant positive correlation between EMPs and glycated hemoglobin (HbA1c) levels was observed, and EMPs were identified as independent predictors of endothelial dysfunction (reduced flow-mediated dilation of brachial artery and elevated brachial ankle pulse wave velocity) in diabetic patients (7). Feng et al (8) and Ishida et al (9) showed significantly elevated levels of circulating MPs from endothelial origin in streptozotocin-induced diabetic rats, compared to non-diabetic rats (8,9).…”