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Here, we hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and\/or inhibition of Rho kinase underlies cystamine vasodilatation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used rat mesenteric small arteries and RT\u2010PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup> ([Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>), K<jats:sup>+<\/jats:sup> currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain, in our experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>RT\u2010PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration\u2010dependently inhibited responses to phenylephrine, 5\u2010HT and U46619 and for extracellular potassium. Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of PLC suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub> in phenylephrine\u2010contracted arteries. In potassium\u2010contracted arteries, cystamine induced less relaxation without changing [Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>]<jats:sub>i<\/jats:sub>, and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of K<jats:sub>v<\/jats:sub>7 channels, XE991 and linopirdine, inhibited cystamine relaxation and increases in voltage\u2010dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1\u2010Thr<jats:sup>855<\/jats:sup> phosphorylation, but only Y27632 reduced phenylephrine\u2010induced increases in MYPT1\u2010Thr<jats:sup>855<\/jats:sup> and myosin regulatory light chain phosphorylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Cystamine induced vasodilatation by inhibition of receptor\u2010coupled TG2, leading to opening of K<jats:sub>v<\/jats:sub> channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13393","type":"journal-article","created":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T06:02:16Z","timestamp":1448431336000},"page":"839-855","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Involvement of transglutaminase 2 and voltage\u2010gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries"],"prefix":"10.1111","volume":"173","author":[{"given":"Morten","family":"Engholm","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Est\u00e9fano","family":"Pinilla","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susie","family":"Mogensen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Matchkov","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise R\u00f8ge","family":"Hedegaard","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Mulvany","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Simonsen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology Aarhus University  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M807746200"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.110.085506"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13349"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13354"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017667108"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000151333.56089.66"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04140.x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.100040"},{"key":"e_1_2_10_10_1","article-title":"Exploring arterial smooth muscle Kv7 potassium channel function using patch clamp electrophysiology and pressure myography","volume":"67","author":"Brueggemann LI","year":"2012","journal-title":"J Vis Exp"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.577bk.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi061787u"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-20-08942.2002"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.214601"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000106465"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000327773"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R109.059972"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(97)00657-1"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(02)02182-5"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01928788"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2009.11.005"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj20021234"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703086"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00977.2005"},{"key":"e_1_2_10_25_1","unstructured":"Hedegaard ER Mogensen S&Simonsen U. 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