Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction
Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction
复制标题
DOI：
10.1152/ajpheart.00201.2014
复制
发表时间：
2014-12-15
影响因子：
4.8
通讯作者：
Stokes, Karen Y.
中科院分区：
文献类型：
--
作者：
Khoretonenko, Mikhail V.;Brunson, Jerry L.;Stokes, Karen Y.
巨细胞病毒（CMV）感染了世界上大多数人口。它与心血管疾病有关，诱导微血管功能障碍，并与高胆固醇血症协同作用，促进白细胞和血小板在小静脉中的募集。虽然血小板和血小板相关P-选择素有助于心血管疾病炎症，但它们在CMV诱导的血管反应中的作用尚不清楚。我们评估了血小板在巨细胞病毒诱导的微血管功能障碍中的作用，通过消耗血小板和开发血小板P-选择素缺乏的骨髓嵌合小鼠。野生型和嵌合小鼠腹腔内接受模拟或鼠（m）CMV。5周后，将一些小鼠转为高胆固醇饮食（HC），以研究mCMV和HC之间的协同作用。11周时检测小动脉血管舒张和小静脉白细胞和供体血小板的募集。有或没有HC的mCMV引起显著的小动脉内皮功能障碍。血小板耗竭恢复正常的血管舒张mCMV-HC，但不是mCMV-ND小鼠，而保护血小板P-选择素嵌合体在两组中看到。仅mCMV + HC增加了小静脉中的白细胞和血小板募集。白细胞粘附减少到模拟水平的急性血小板耗竭，但只有部分减少血小板P-选择素嵌合体。来自mCMV-HC小鼠的血小板，以及在较小程度上来自mCMV-ND但不是mock-HC小鼠的血小板在mCMV-HC受体中显示出显著的粘附。我们的研究结果暗示血小板的作用，通过P-选择素，在CMV诱导的小动脉功能障碍，并建议HC的加入导致血小板依赖性，炎症浸润，只有部分血小板P-选择素依赖。CMV似乎比HC对血小板有更强的激活作用，可能是脆弱患者的另一个治疗靶点。
Cytomegalovirus (CMV) infects a majority of the population worldwide. It has been implicated in cardiovascular disease, induces microvascular dysfunction, and synergizes with hypercholesterolemia to promote leukocyte and platelet recruitment in venules. Although platelets and platelet-associated P-selectin contribute to cardiovascular disease inflammation, their role in CMV-induced vascular responses is unknown. We assessed the role of platelets in CMV-induced microvascular dysfunction by depleting platelets and developing bone marrow chimeric mice deficient in platelet P-selectin. Wild-type and chimeric mice received mock or murine (m) CMV intraperitoneally. Five weeks later, some mice were switched to a high-cholesterol diet (HC) to investigate the synergism between mCMV and HC. Arteriolar vasodilation and recruitment of leukocytes and donor platelets in venules were measured at 11wk. mCMV with or without HC caused significant endothelial dysfunction in arterioles. Platelet depletion restored normal vasodilation in mCMV-HC but not mCMV-ND mice, whereas protection was seen in both groups for platelet P-selectin chimeras. Only mCMV + HC elevated leukocyte and platelet recruitment in venules. Leukocyte adhesion was reduced to mock levels by acute platelet depletion but was only partially decreased in platelet P-selectin chimeras. Platelets from mCMV-HC mice and, to a lesser extent, mCMV-ND but not mock-HC mice showed significant adhesion in mCMV-HC recipients. Our findings implicate a role for platelets, acting through P-selectin, in CMV-induced arteriolar dysfunction and suggest that the addition of HC leads to a platelet-dependent, inflammatory infiltrate that is only partly platelet P-selectin dependent. CMV appeared to have a stronger activating influence than HC on platelets and may represent an additional therapeutic target in vulnerable patients.