Gretchen M Koller1, Christopher Schafer2, Scott S Kemp1, Kalia N Aguera1, Prisca K Lin1, Joshua C Forgy1, Courtney T Griffin2,3, George E Davis1. 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 (C.S., C.T.G.), University of Oklahoma Health Sciences Center. 3. Department of Cell Biology (C.T.G.), University of Oklahoma Health Sciences Center.
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 (intercellular adhesion molecule-1), phospho-p38, and phospho-MLC2 (myosin light chain-2) 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.
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 (intercellular adhesion molecule-1), phospho-p38, and phospho-MLC2 (myosin light chain-2) 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.
Authors: Christopher M Schafer; Jami M Gurley; Katarzyna Kurylowicz; Prisca K Lin; Wen Chen; Michael H Elliott; George E Davis; Faizah Bhatti; Courtney T Griffin Journal: Proc Natl Acad Sci U S A Date: 2020-10-05 Impact factor: 11.205
Authors: Yu Zhao; Xiangyang Zhu; Lei Zhang; Christopher M Ferguson; Turun Song; Kai Jiang; Sabena M Conley; James D Krier; Hui Tang; Ishran Saadiq; Kyra L Jordan; Amir Lerman; Lilach O Lerman Journal: Stem Cells Dev Date: 2020-08-03 Impact factor: 3.272
Authors: Reyaz Hassan Mir; Goutami Godavari; Nasir Ali Siddiqui; Bilal Ahmad; Ramzi A Mothana; Riaz Ullah; Omer M Almarfadi; Sanjay M Jachak; Mubashir Hussain Masoodi Journal: Drug Des Devel Ther Date: 2021-02-04 Impact factor: 4.162
Authors: Zheying Sun; Scott S Kemp; Prisca K Lin; Kalia N Aguera; George E Davis Journal: Arterioscler Thromb Vasc Biol Date: 2021-12-09 Impact factor: 8.311
Authors: Prisca K Lin; Jocelynda Salvador; Jun Xie; Kalia N Aguera; Gretchen M Koller; Scott S Kemp; Courtney T Griffin; George E Davis Journal: Am J Pathol Date: 2021-09-24 Impact factor: 4.307