Journal
CELLS
Volume 10, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/cells10051008
Keywords
hypoxia; extracellular matrix; hyaluronan; collagen; fibrillogenesis; elastin; fibulin 5; ceruloplasmin; TGFΒ fibromodulin; ADAMTS15; GLUT3
Categories
Funding
- Verein zur Forderung der Lymphologie e.V.
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Lymphedema is a chronic disease affecting millions globally, with no pharmacological treatment available. The disease is characterized by swelling, fibrosis, and collagen accumulation in affected tissues. This study found that hypoxia may contribute to fibrosis in lymphatic endothelial cells (LECs), with hypoxic LECs showing a high ability to alter the extracellular matrix.
Lymphedema (LE) affects millions of people worldwide. It is a chronic progressive disease with massive development of fibrosclerosis when untreated. There is no pharmacological treatment of lymphedema. The disease is associated with swelling of the interstitium of the affected organ, mostly arm or leg, impressive development of adipose tissue, fibrosis and sclerosis with accumulation of huge amounts of collagen, and Papillomatosis cutis. Malnutrition and reduced oxygenation of the affected tissues is a hallmark of lymphedema. Here, we investigated if the hypoxia of lymphatic endothelial cells (LECs) might contribute to fibrosis. We applied RNASeq and qPCR to study the concordant changes of the exome of three human foreskin-derived LEC isolates after 4 days of hypoxia (1% O-2) vs. normoxia (21% O-2). Of the approximately 16,000 genes expressed in LECs, 162 (1%) were up- or down-regulated by hypoxia. Of these, 21 genes have important functions in the production or modification of the extracellular matrix (ECM). In addition to the down-regulation of elastin, we found up-regulation of druggable enzymes and regulators such as the long non-coding RNA H19, inter-alpha-trypsin inhibitor heavy chain family member 5 (ITIH5), lysyl-oxidase (LOX), prolyl 4-hydroxylase subunit alpha 1 (P4HA1), procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2), and others that are discussed in the paper. Initial lymphatics do not produce a continuous basement membrane; however, our study shows that hypoxic LECs have an unexpectedly high ability to alter the ECM.
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