{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T22:47:16Z","timestamp":1791154036368,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2017,1,20]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Atherosclerotic-arterial occlusions decrease tissue perfusion causing ischemia to lower limbs in patients with peripheral arterial disease (PAD). Ischemia in muscle induces an angiogenic response, but the magnitude of this response is frequently inadequate to meet tissue perfusion requirements. Alternate splicing in the exon-8 of vascular endothelial growth factor (VEGF)-A results in production of proangiogenic VEGF\n                      <jats:sub>xxx<\/jats:sub>\n                      a isoforms (VEGF\n                      <jats:sub>165<\/jats:sub>\n                      a, 165 for the 165 amino acid product) and antiangiogenic VEGF\n                      <jats:sub>xxx<\/jats:sub>\n                      b (VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b) isoforms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      The antiangiogenic VEGF\n                      <jats:sub>xxx<\/jats:sub>\n                      b isoforms are thought to antagonize VEGF\n                      <jats:sub>xxx<\/jats:sub>\n                      a isoforms and decrease activation of VEGF receptor-2 (VEGFR2), hereunto considered the dominant receptor in postnatal angiogenesis in PAD. Our data will show that VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b inhibits VEGFR1 signal transducer and activator of transcription (STAT)-3 signaling to decrease angiogenesis in human and experimental PAD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      In human PAD versus control muscle biopsies, VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b: (1) is elevated, (2) is bound higher (versus VEGF\n                      <jats:sub>165<\/jats:sub>\n                      a) to VEGFR1 not VEGFR2, and (3) levels correlated with decreased VEGFR1, not VEGFR2, activation. In experimental PAD, delivery of an isoform-specific monoclonal antibody to VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b versus control antibody enhanced perfusion in animal model of severe PAD (Balb\/c strain) without activating VEGFR2 signaling but with increased VEGFR1 activation. Receptor pull-down experiments demonstrate that VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b inhibition versus control increased VEGFR1\u2013STAT3 binding and STAT3 activation, independent of Janus-activated kinase-1)\/Janus-activated kinase-2. Using VEGFR1\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mice that could not increase VEGFR1 after ischemia, we confirm that VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b decreases VEGFR1\u2013STAT3 signaling to decrease perfusion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Our results indicate that VEGF\n                      <jats:sub>165<\/jats:sub>\n                      b prevents activation of VEGFR1\u2013STAT3 signaling by VEGF\n                      <jats:sub>165<\/jats:sub>\n                      a and hence inhibits angiogenesis and perfusion recovery in PAD muscle.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.116.309516","type":"journal-article","created":{"date-parts":[[2016,12,14]],"date-time":"2016-12-14T23:01:21Z","timestamp":1481756481000},"page":"282-295","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":88,"title":["VEGF\n                    <sub>165<\/sub>\n                    b Modulates Endothelial VEGFR1\u2013STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease"],"prefix":"10.1161","volume":"120","author":[{"given":"Vijay Chaitanya","family":"Ganta","sequence":"first","affiliation":[{"name":"From the Cardiovascular Research Center (V.C.G., M.C., B.H.A.), Department of Biology (A.K.), and Department of Cardiovascular Medicine, University of Virginia, Charlottesville (B.H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Choi","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Center (V.C.G., M.C., B.H.A.), Department of Biology (A.K.), and Department of Cardiovascular Medicine, University of Virginia, Charlottesville (B.H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kutateladze","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Center (V.C.G., M.C., B.H.A.), Department of Biology (A.K.), and Department of Cardiovascular Medicine, University of Virginia, Charlottesville (B.H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Annex","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Center (V.C.G., M.C., B.H.A.), Department of Biology (A.K.), and Department of Cardiovascular Medicine, University of Virginia, Charlottesville (B.H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2013.70"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccl.2014.09.008"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.4065\/mcp.2010.0133"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00125.2014"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.4062\/biomolther.2013.113"},{"key":"e_1_3_5_7_2","first-page":"469","article-title":"Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis.","volume":"39","author":"Shibuya M","year":"2006","unstructured":"Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol. 2006;39:469\u2013478.","journal-title":"J Biochem Mol Biol"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1911"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0131445"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.174128"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094540"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000093398.16124.29"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(03)00102-9"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1522-1865(02)00158-0"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1177\/1358863X11436334"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-0934"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6577"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3703"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0068399"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2505"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404984102"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/376062a0"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00047.2007"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00070.2010"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.736447"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00803.2014"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.000860"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.103127"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.2011.02925.x"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2007.02.011"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403667"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.257"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)47116-5"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.04.017"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.13.3015"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-013-9413-2"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0202"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181c9c05b"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105533"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-9-320"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.008171"},{"key":"e_1_3_5_42_2","first-page":"213","article-title":"Flt-1 but not KDR\/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor.","volume":"7","author":"Sawano A","year":"1996","unstructured":"Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M. Flt-1 but not KDR\/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Differ. 1996;7:213\u2013221.","journal-title":"Cell Growth Differ"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-4360"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1938"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.305476"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.12.014"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.116.309516","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:54:51Z","timestamp":1715558091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.116.309516"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,20]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2017,1,20]]}},"alternative-id":["10.1161\/CIRCRESAHA.116.309516"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.116.309516","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727112295.793529154","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,20]]},"assertion":[{"value":"2016-07-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}