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Arterioscler Thromb Vasc Biol. 2019 Dec 19:ATVBAHA119313536. doi: 10.1161/ATVBAHA.119.313536. [Epub ahead of print]

Proinflammatory Mediators, IL (Interleukin)-1β, TNF (Tumor Necrosis Factor) α, and Thrombin Directly Induce Capillary Tube Regression.

Author information

1
From the Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida School of Medicine, Tampa (G.M.K., S.S.K., K.N.A., P.K.L., J.C.F., G.E.D.).
2
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center. (C.S., C.T.G.).
3
Department of Cell Biology, University of Oklahoma Health Sciences Center. (C.T.G.).

Abstract

OBJECTIVE:

In this work, we examine the molecular basis for capillary tube regression and identify key proregressive factors, signaling pathways, and pharmacological antagonists of this process. Approach and Results: We demonstrate that the proinflammatory mediators, IL (interleukin)-1β, TNF (tumor necrosis factor) α, and thrombin, singly and in combination, are potent regulators of capillary tube regression in vitro. These proregressive factors, when added to endothelial cell-pericyte cocultures, led to selective loss of endothelial cell-lined tube networks, with retention and proliferation of pericytes despite the marked destruction of adjacent capillary tubes. Moreover, treatment of macrophages with the TLR (toll-like receptor) agonists Pam3CSK4 and lipopolysaccharide generates conditioned media with marked proregressive activity, that is completely blocked by a combination of neutralizing antibodies directed to IL-1β and TNFα but not to other factors. The same combination of blocking antibodies, as well as the anti-inflammatory cytokine IL-10, interfere with macrophage-dependent hyaloid vasculature regression in mice suggesting that proinflammatory cytokine signaling regulates capillary regression in vivo. In addition, we identified a capillary regression signaling signature in endothelial cells downstream of these proregressive agents that is characterized by increased levels of ICAM-1, phospho-p38, and phospho-MLC2 and decreased levels of phospho-Pak2, acetylated tubulin, phospho-cofilin, and pro-caspase3. Finally, we identified combinations of pharmacological agents (ie, FIST and FISTSB) that markedly rescue the proregressive activities of IL-1β, TNFα, and thrombin, individually and in combination.

CONCLUSIONS:

Overall, these new studies demonstrate that the major proinflammatory mediators, IL-1β, TNFα, and thrombin, are key regulators of capillary tube regression-a critical pathological process regulating human disease.

KEYWORDS:

endothelial cells; interleukins; pericytes; thrombin; tumor necrosis factor-α

PMID:
31852224
DOI:
10.1161/ATVBAHA.119.313536

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