Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, PA, 17033, USA.
Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA.
J Physiol. 2019 Feb;597(3):781-798. doi: 10.1113/JP277312. Epub 2019 Jan 9.
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.
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.
循环微粒（MPs）在许多心血管疾病中升高，并被认为是疾病预后的生物标志物；然而，目前对 MPs 功能的认识主要来自体外研究，其对血管炎症和疾病进展的确切影响仍不清楚。使用糖尿病大鼠模型，我们发现与正常大鼠相比，糖尿病大鼠血浆中的 MPs 增加了>130 倍，其中大多数以聚集体的形式循环，表达多种细胞标志物，并大量外化磷脂酰丝氨酸；血管图像说明了 MPs 的发生和在糖尿病大鼠微血管中的表现。使用联合的单个微血管灌注和系统交叉输血方法，我们描述了糖尿病 MPs 如何在血管中传播炎症，并将正常微血管转化为糖尿病大鼠微血管中观察到的炎症表型。我们从类似于糖尿病患者的条件的动物研究中得出的观察结果，为 MPs 介导的糖尿病相关多器官微血管功能障碍的发病机制提供了机制上的见解。
在各种心血管疾病中，微粒（MPs），即在细胞激活过程中释放的膜衍生小泡，在循环中显著增加。这些 MPs 被认为在调节细胞功能方面发挥着多种作用。然而，目前对 MPs 功能的认识主要来自体外研究。疾病诱导的 MPs 对血管炎症和疾病进展的确切影响仍不清楚。在这项研究中，我们使用具有特征明确的微血管功能的链脲佐菌素诱导的糖尿病大鼠模型，研究了循环 MPs 的发生、特征和功能作用。我们的研究表明，与正常大鼠相比，糖尿病大鼠血浆中的 MPs 增加了>130 倍。这些 MPs 中的大多数来自血小板、白细胞和内皮细胞（EC），并以聚集体的形式循环。糖尿病 MPs 比正常 MPs 显示出更大的外化磷脂酰丝氨酸（PS）。当将糖尿病血浆或分离的糖尿病 MPs 灌注到正常微血管中或系统地输注到正常大鼠中时，MPs 立即粘附在内皮细胞上，随后介导白细胞粘附。这些微血管随后对炎症介质的通透性反应增强，复制了在糖尿病大鼠中观察到的微血管表现。当从糖尿病血浆中去除 MPs 或当用脂质结合蛋白， annexin V 预处理糖尿病 MPs 时，这些作用被阻断，表明外化 PS 是介导 MPs 与内皮细胞和白细胞相互作用的关键。我们的研究表明，糖尿病血浆中升高的 MPs 通过其粘附表面积极参与血管炎症的传播，为糖尿病患者常见的多器官血管功能障碍的发病机制提供了机制上的见解。
