TNF-α drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

Abstract

Inflammation is associated with blood vessel and lymphatic vessel proliferation and remodeling. The microvasculature of the mouse trachea provides an ideal opportunity to study this process, as Mycoplasma pulmonis infection of mouse airways induces widespread and sustained vessel remodeling, including enlargement of capillaries into venules and lymphangiogenesis. Although the mediators responsible for these vascular changes in mice have not been identified, VEGF-A is known not to be involved. Here, we sought to determine whether TNF-α drives the changes in blood vessels and lymphatics in M. pulmonis-infected mice. The endothelial cells, but not pericytes, of blood vessels, but not lymphatics, were immunoreactive for TNF receptor 1 (TNF-R1) and lymphotoxin B receptors. Most TNF-R2 immunoreactivity was on leukocytes. Infection resulted in a large and sustained increase in TNF-α expression, as measured by real-time quantitative RT-PCR, and smaller increases in lymphotoxins and TNF receptors that preceded vessel remodeling. Substantially less vessel remodeling and lymphangiogenesis occurred when TNF-α signaling was inhibited by a blocking antibody or was silenced in Tnfr1 -/-mice. When administered after infection was established, the TNF-α-specific antibody slowed but did not reverse blood vessel remodeling and lymphangiogenesis. The action of TNF-α on blood vessels is probably mediated through direct effects on endothelial cells, but its effects on lymphangiogenesis may require inflammatory mediators from recruited leukocytes. We conclude that TNF-α is a strong candidate for a mediator that drives blood vessel remodeling and lymphangiogenesis in inflammation. IntroductionA wide spectrum of changes in blood vessels occurs in inflammation. Acute inflammation is accompanied by reversible vasodilatation, increased blood flow, plasma extravasation, and leukocyte adhesion and transmigration. In chronic inflammation, characteristic of asthma, obstructive pulmonary disease, rheumatoid arthritis, psoriasis, and inflammatory bowel disease, blood vessels and lymphatic vessels proliferate and undergo remodeling with changes in structural, functional, and molecular phenotypes. As part of the remodeling, capillaries enlarge and transform into venules that contribute to leukocyte adhesion and migration unpublished observations). Lymphatic vessels not only sprout and proliferate but also enlarge and undergo phenotypic changes (4, 5).Although much attention has been devoted to sprouting angiogenesis in cancer, less is known about the factors that govern vascular remodeling in inflammation. The microvasculature of the mouse trachea presents an opportunity to study such factors because it (a) has a regular segmented 2D architecture repeated between and over the tracheal cartilage rings; (b) can be subjected to short-and long-lasting inflammatory stimuli (6); and (c) is a site of angiogenesis, vascular remodeling, and lymphangiogenesis after infection by Mycoplasma pulmonis. A conspicuous early feature of vascular remodeling in the ...

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TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

“…It is unclear why VEGF-C and -D are differentially regulated in TNF-a-activated macrophages. In an airway inflammation mouse model, TNF-a has been shown to remodel blood vessels and lymphatic vessels 19 . Its vascular remodelling function on blood vessels is mediated by TNFR1 expressed in endothelial cells, whereas remodelling of lymphatics is probably achieved by recruitment of leukocytes since LECs lack TNFR1 expression 19 .…”

“…In an airway inflammation mouse model, TNF-a has been shown to remodel blood vessels and lymphatic vessels 19 . Its vascular remodelling function on blood vessels is mediated by TNFR1 expressed in endothelial cells, whereas remodelling of lymphatics is probably achieved by recruitment of leukocytes since LECs lack TNFR1 expression 19 . Our present findings, however, show both in vitro isolated mouse and hLECs that express TNFR1, which was further validated in several in vivo experimental models.…”

“…The vascular endothelial growth factor (VEGF)-C-VEGF receptor 3 (VEGFR3) signalling as the key lymphangiogenic pathway is crucially involved in inflammatory lymphangiogenesis 13 . TNF-a has recently been reported to mediate blood and lymphatic vessel remodelling in a mouse airway inflammation model 19 . TNF-a has also been reported to inhibit lymphatic endothelial cell (LEC) proliferation 20 , whereas the opposing effect of TNF-a in combination with angiopoietin-2 on LEC proliferation was also reported 21 .…”