Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium.

Abstract

In chronic wounds, hypoxia seriously undermines tissue repair processes by altering the balances between pro-angiogenic 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/TIMP 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.

• Authors: Nicoletta Basilico, Chiara Magnetto, Sarah D'Alessandro, Alice Panariti, Ilaria Rivolta, Tullio Genova, Amina Khadjavi, Giulia Rossana Gulino, Monica Argenziano, Marco Soster, Roberta Cavalli, Giuliana Giribaldi, Caterina Guiot, Mauro Prato
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 288 Issue 3 Pg. 330-8 (Nov 01 2015) ISSN: 1096-0333 [Electronic] United States
• PMID: 26276311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Angiogenesis Inducing Agents
• Dextrans
• TIMP1 protein, human
• TIMP2 protein, human
• Tissue Inhibitor of Metalloproteinase-1
• Tissue Inhibitor of Metalloproteinase-2
• Chitosan
• Gelatinases
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Oxygen

Topics

• Angiogenesis Inducing Agents (chemistry, pharmacology)
• Cell Line
• Cell Survival (drug effects)
• Chitosan (chemistry, pharmacology)
• Dextrans (chemistry, pharmacology)
• Endothelial Cells (drug effects, metabolism)
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Extracellular Matrix (drug effects, metabolism)
• Gelatinases (metabolism)
• Humans
• Hypoxia (drug therapy)
• Keratinocytes (drug effects, metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Nanostructures (chemistry)
• Oxygen (chemistry, pharmacology)
• Phenotype
• Skin (drug effects, metabolism)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)
• Wound Healing (drug effects)