{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T19:12:44Z","timestamp":1788721964598,"version":"build-2803163510"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,10,15]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Alternative splicing in the eighth exon C\u2010terminus of VEGF\u2010A (vascular endothelial growth factor\u2010A) results in the formation of proangiogenic VEGF\n              <jats:sub>165<\/jats:sub>\n              a and antiangiogenic VEGF\n              <jats:sub>165<\/jats:sub>\n              b isoforms. The only known difference between these 2 isoform families is a 6\u2010amino acid switch from CDKPRR (in VEGF\n              <jats:sub>165<\/jats:sub>\n              a) to SLTRKD (in VEGF\n              <jats:sub>165<\/jats:sub>\n              b). We have recently shown that VEGF\n              <jats:sub>165<\/jats:sub>\n              b can induce VEGFR2\u2010activation but fails to induce VEGFR1 (VEGF receptor 1)\u2010activation. The molecular mechanisms that regulate VEGF\n              <jats:sub>165<\/jats:sub>\n              b's ability toward differential VEGFR2 versus VEGFR1 activation\/inhibition are not yet clear.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Hypoxia serum starvation was used as an in\u00a0vitro peripheral artery disease model. Unilateral single ligation of the femoral artery was used as a preclinical peripheral artery disease model. VEGFR1 activating ligands have 2 arginine (RR) residues in their eighth exon C\u2010terminus, that were replaced by lysine\u2010aspartic acid (KD) in VEGF\n              <jats:sub>165<\/jats:sub>\n              b. A synthetic anti\u2010angiogenic VEGF\n              <jats:sub>165<\/jats:sub>\n              b splice variant in which the KD residues were switched to RR (VEGF\n              <jats:sub>165<\/jats:sub>\n              b\n              <jats:sub>KD\u2192RR<\/jats:sub>\n              ) activated both VEGFR1\u2010 and VEGFR2\u2010signaling pathways to induce ischemic\u2010endothelial cell angiogenic capacity in\u00a0vitro and enhance perfusion recovery in a severe experimental\u2010peripheral artery disease model significantly higher than VEGF\n              <jats:sub>165<\/jats:sub>\n              a. Phosphoproteome arrays showed that the therapeutic efficacy of VEGF\n              <jats:sub>165<\/jats:sub>\n              b\n              <jats:sub>KD\u2192RR<\/jats:sub>\n              over VEGF\n              <jats:sub>165<\/jats:sub>\n              a is due to its ability to induce P38\u2010activation in ischemic endothelial cells.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Our data shows that the KD residues regulate VEGF\n              <jats:sub>165<\/jats:sub>\n              b's VEGFR1 inhibitory property but not VEGFR2. Switching these KD residues to RR resulted in the formation of a synthetic\/recombinant VEGF\n              <jats:sub>165<\/jats:sub>\n              b\n              <jats:sub>KD\u2192RR<\/jats:sub>\n              isoform that has the ability to activate both VEGFR1\u2010 and VEGFR2\u2010signaling and induce ischemic\u2010endothelial cell angiogenic and proliferative capacity that matched the angiogenic requirement necessary to achieve perfusion recovery in a severe experimental\u2010peripheral artery disease model.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.034304","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T11:15:46Z","timestamp":1728645346000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Synthetic Antiangiogenic Vascular Endothelial Growth Factor\u2014A Splice Variant Revascularizes Ischemic Muscle in Peripheral Artery Disease"],"prefix":"10.1161","volume":"13","author":[{"given":"Adarshini","family":"Raja","sequence":"first","affiliation":[{"name":"Medical College of Georgia Augusta University Augusta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2967-8320","authenticated-orcid":false,"given":"Vijay","family":"Ganta","sequence":"additional","affiliation":[{"name":"Vascular Biology Center and Department of Medicine Augusta University Augusta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.semvascsurg.2021.02.005"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.endonu.2016.03.007"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.01.054"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1709326"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/Circresaha.121.318266"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2013.70"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvs136"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.34.1785"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-006-9055-8"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.303776.117"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1911"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6813"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.30.21217"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2505"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0068399"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-0934"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-4360"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604308"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-9-320"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6577"},{"key":"e_1_3_1_22_2","first-page":"626","article-title":"VEGF165b, an endogenous C\u2010terminal splice variant of VEGF, inhibits retinal neovascularization in mice","volume":"12","author":"Konopatskaya O","year":"2006","unstructured":"Konopatskaya O, Churchill AJ, Harper SJ, Bates DO, Gardiner TA. 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