Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium
Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium
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DOI：
10.1016/j.taap.2015.08.005
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发表时间：
2015-11-01
影响因子：
3.8
通讯作者：
Prato, Mauro
中科院分区：
文献类型：
--
作者：
Basilico, Nicoletta;Magnetto, Chiara;Prato, Mauro
在慢性伤口中，缺氧通过改变从周围细胞释放的促血管生成蛋白水解酶（基质金属蛋白酶，MMPs）及其抑制剂（金属蛋白酶组织抑制剂，TIMPs）之间的平衡而严重破坏组织修复过程。最近，我们已经表明，在人单核细胞缺氧减少MMP-9和增加TIMP-1，而不影响TIMP-2的分泌，而在人角质形成细胞中，它减少MMP-2，MMP-9，和TIMP-2，而不影响TIMP-1的释放。如果更好地理解细胞环境的表型，慢性伤口可能会被新的氧合化合物靶向，如壳聚糖或葡聚糖壳和2 H，3 H-癸基戊烷核载氧纳米滴（OLN）。在这里，我们研究了缺氧和葡聚糖壳OLNs的促血管生成的表型和行为的人真皮微血管内皮细胞（HMEC-1细胞系），另一个细胞群体在伤口愈合过程中发挥关键作用的影响。常氧HMEC-1组成性释放MMP-2、TIMP-1和TIMP-2蛋白，但不释放MMP-9。缺氧增强MMP-2和减少TIMP-1分泌，而不影响TIMP-2水平，并损害细胞迁移和侵入细胞外基质的能力。当被HMEC-1摄取时，无毒OLN消除缺氧的作用，恢复常氧MMP/IIMP水平，并促进细胞迁移、基质侵袭和微血管形成。这些效果特别依赖于OLN核心的持续时间的氧扩散，因为它们不是通过无氧纳米液滴或氧饱和溶液实现的。总的来说，这些数据提供了新的信息，缺氧对真皮内皮细胞的影响，并支持的假设，OLNs可能被用作有效的辅助工具，以促进慢性伤口愈合过程。(C)2015 Elsevier Inc. All rights reserved.
In chronic wounds, hypoxia seriously undermines tissue repair processes by altering the balances between proangiogenic proteolytic enzymes (matrix metalloproteinases, MMPs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) released from surrounding cells. Recently, we have shown that in human monocytes hypoxia reduces MMP-9 and increases TIMP-1 without affecting TIMP-2 secretion, whereas in human keratinocytes it reduces MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. Provided that the phenotype of the cellular environment is better understood, chronic wounds might be targeted by new oxygenating compounds such as chitosan- or dextran-shelled and 2H,3H-decafluoropentane-cored oxygen-loaded nanodroplets (OLNs). Here, we investigated the effects of hypoxia and dextran-shelled OLNs on the pro-angiogenic phenotype and behavior of human dermal microvascular endothelium (HMEC-1 cell line), another cell population playing key roles during wound healing. Normoxic HMEC-1 constitutively released MMP-2, TIMP-1 and TIMP-2 proteins, but not MMP-9. Hypoxia enhanced MMP-2 and reduced TIMP-1 secretion, without affecting TIMP-2 levels, and compromised cell ability to migrate and invade the extracellular matrix. When taken up by HMEC-1, nontoxic OLNs abrogated the effects of hypoxia, restoring normoxic MMP/IIMP levels and promoting cell migration, matrix invasion, and formation of microvessels. These effects were specifically dependent on time-sustained oxygen diffusion from OLN core, since they were not achieved by oxygen-free nanodroplets or oxygen-saturated solution. Collectively, these data provide new information on the effects of hypoxia on dermal endothelium and support the hypothesis that OLNs might be used as effective adjuvant tools to promote chronic wound healing processes. (C) 2015 Elsevier Inc. All rights reserved.