{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:07:14Z","timestamp":1785920834312,"version":"3.56.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We used mouse models of constitutive endothelial cell\u2013specific Arf6 deletion (Arf6\n                      <jats:sup>f\/\u2212<\/jats:sup>\n                      Tie2Cre\n                      <jats:sup>+<\/jats:sup>\n                      ) and tamoxifen-inducible Arf6 knockout (Arf6\n                      <jats:sup>f\/f<\/jats:sup>\n                      Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere\u2013based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside\u2013mediated vasodilation. Endothelial cell\u2013specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow\u2013fed mice and glucose intolerance in high-fat diet\u2013fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.123.319375","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T05:01:38Z","timestamp":1711602098000},"page":"1101-1113","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice"],"prefix":"10.1161","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8263-0628","authenticated-orcid":true,"given":"Md Torikul","family":"Islam","sequence":"first","affiliation":[{"name":"Department of Nutrition and Integrative Physiology (M.T.I., S.I.B., A.J.D., W.L.H., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjin","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Department of Internal Medicine (J.C., S.A., D.G.M., R.C.B., J.M., A.J.D., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-2186","authenticated-orcid":true,"given":"Shanena","family":"Allen","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Department of Internal Medicine (J.C., S.A., D.G.M., R.C.B., J.M., A.J.D., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6111-9337","authenticated-orcid":true,"given":"Denisse G.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Department of Internal Medicine (J.C., S.A., D.G.M., R.C.B., J.M., A.J.D., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1440-8122","authenticated-orcid":true,"given":"Samuel I.","family":"Bloom","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology (M.T.I., S.I.B., A.J.D., W.L.H., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Colton","family":"Bramwell","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Department of Internal Medicine (J.C., S.A., D.G.M., R.C.B., J.M., A.J.D., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Mitton","sequence":"additional","affiliation":[{"name":"Division of Geriatrics, Department of Internal Medicine (J.C., S.A., D.G.M., R.C.B., J.M., A.J.D., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4435-4022","authenticated-orcid":true,"given":"Andrew G.","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, Kansas State University, Manhattan 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University of Utah, Salt Lake City."},{"name":"Department of Biochemistry (A.J.D.), The University of Utah, Salt Lake City."},{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute (A.J.D., L.A.L.), The University of Utah, Salt Lake City."},{"name":"Veteran\u2019s Affairs Medical Center-Salt Lake City, Geriatric Research and Clinical Center, UT (A.J.D., L.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9950-1435","authenticated-orcid":true,"given":"William L.","family":"Holland","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Integrative Physiology (M.T.I., S.I.B., A.J.D., W.L.H., L.A.L.), The University of Utah, Salt Lake City."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2138-1450","authenticated-orcid":true,"given":"Lisa A.","family":"Lesniewski","sequence":"additional","affiliation":[{"name":"Department of Nutrition and 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