{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:18:11Z","timestamp":1790036291626,"version":"4.0.1"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>We demonstrate that the proinflammatory mediators, IL (interleukin)-1\u03b2, TNF (tumor necrosis factor) \u03b1, and thrombin, singly and in combination, are potent regulators of capillary tube regression in vitro. These proregressive factors, when added to endothelial cell\u2013pericyte 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-1\u03b2 and TNF\u03b1 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-1\u03b2, TNF\u03b1, and thrombin, individually and in combination.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Overall, these new studies demonstrate that the major proinflammatory mediators, IL-1\u03b2, TNF\u03b1, and thrombin, are key regulators of capillary tube regression\u2014a critical pathological process regulating human disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.119.313536","type":"journal-article","created":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T10:00:29Z","timestamp":1576749629000},"page":"365-377","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Proinflammatory Mediators, IL (Interleukin)-1\u03b2, TNF (Tumor Necrosis Factor) \u03b1, and Thrombin Directly Induce Capillary Tube Regression"],"prefix":"10.1161","volume":"40","author":[{"given":"Gretchen M.","family":"Koller","sequence":"first","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Schafer","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (C.S., C.T.G.), University of Oklahoma Health Sciences Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott S.","family":"Kemp","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalia N.","family":"Aguera","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prisca K.","family":"Lin","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Forgy","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney T.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (C.S., C.T.G.), University of Oklahoma Health Sciences Center."},{"name":"Department of Cell Biology (C.T.G.), University of Oklahoma Health Sciences Center."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E.","family":"Davis","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2183"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.11.007"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386041-5.00003-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3109\/03008207.2015.1066781"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2016.04.005"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c160048"},{"key":"e_1_3_4_8_2","first-page":"1","volume-title":"In: Biophysical Regulation of Vascular Differentiation and Assembly","author":"Davis GE","year":"2018","unstructured":"Davis, GE. 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