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However, the downstream events that mediate the strengthening of the endothelial cell (EC) barrier via adenosine signaling are largely unknown. In the current study, we tested the overall hypothesis that adenosine\u2010induced Rac1 activation and EC barrier enhancement is mediated by Gs\u2010dependent stimulation of cAMP\u2010dependent Epac1\u2010mediated signaling cascades. Adenoviral transduction of HPAEC with constitutively\u2010active (C\/A) Rac1 (V12Rac1) significantly increases transendothelial electrical resistance (TER) reflecting an enhancement of the EC barrier. Conversely, expression of an inactive Rac1 mutant (N17Rac1) decreases TER reflecting a compromised EC barrier. The adenosine\u2010induced increase in TER was accompanied by activation of Rac1, decrease in contractility (MLC dephosphorylation), but not Rho inhibition. Conversely, inhibition of Rac1 activity attenuates adenosine\u2010induced increase in TER. We next examined the role of cAMP\u2010activated Epac1 and its putative downstream targets Rac1, Vav2, Rap1, and Tiam1. Depletion of Epac1 attenuated the adenosine\u2010induced Rac1 activation and the increase in TER. Furthermore, silencing of Rac1 specific guanine nucleotide exchange factors (GEFs), Vav2 and Rap1a expression significantly attenuated adenosine\u2010induced increases in TER and activation of Rac1. Depletion of Rap1b only modestly impacted adenosine\u2010induced increases in TER and Tiam1 depletion had no effect on adenosine\u2010induced Rac1 activation and TER. Together these data strongly suggest that Rac1 activity is required for adenosine\u2010induced EC barrier enhancement and that the activation of Rac1 and ability to strengthen the EC barrier depends, at least in part, on cAMP\u2010dependent Epac1\/Vav2\/Rap1\u2010mediated signaling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.26281","type":"journal-article","created":{"date-parts":[[2017,11,23]],"date-time":"2017-11-23T05:52:44Z","timestamp":1511416364000},"page":"5736-5746","source":"Crossref","is-referenced-by-count":12,"title":["Extracellular adenosine\u2010induced Rac1 activation in pulmonary endothelium: Molecular mechanisms and barrier\u2010protective role"],"prefix":"10.1002","volume":"233","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7244-5517","authenticated-orcid":false,"given":"Anita","family":"Kovacs\u2010Kasa","sequence":"first","affiliation":[{"name":"Vascular Biology Center Medical College of Georgia at Augusta University Augusta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyung Mi","family":"Kim","sequence":"additional","affiliation":[{"name":"Vascular Biology Center Medical College of Georgia at Augusta University Augusta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Cherian\u2010Shaw","sequence":"additional","affiliation":[{"name":"Vascular Biology Center Medical College of Georgia at Augusta University Augusta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen M.","family":"Black","sequence":"additional","affiliation":[{"name":"Center for Lung Vascular Pathobiology University of Arizona Phoenix Arizona"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Fulton","sequence":"additional","affiliation":[{"name":"Vascular Biology Center Medical College of Georgia at Augusta University Augusta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander D.","family":"Verin","sequence":"additional","affiliation":[{"name":"Vascular Biology Center Medical College of Georgia at Augusta University Augusta Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,3,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200404068"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12175"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000267856.00713.0a"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-6980(98)00065-3"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21819"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2003"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7660com"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20966"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21354"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.03.036"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21913"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1197"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2006.10.002"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8552-x"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309726"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200907135"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00298.2011"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-05-1987"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12076"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/24884"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.91.4.1487"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-117044"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181b060f2"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030891"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01148"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2008.2220"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01596-0"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.141.2.409"},{"issue":"1","key":"e_1_2_8_30_1","first-page":"L172","article-title":"Mechanisms of ionomycin\u2010induced endothelial cell barrier dysfunction","volume":"273","author":"Garcia J. 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