{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:59:11Z","timestamp":1789239551122,"version":"build-2803163510"},"reference-count":95,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,11,19]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Endothelial cells (ECs) use glycolysis to produce energy. In preclinical models of peripheral arterial disease, further activation of EC glycolysis was ineffective or deleterious in promoting hypoxia-dependent angiogenesis, whereas pentose phosphate pathway activation was effective. Hexosamine biosynthesis pathway, pentose phosphate pathway, and glycolysis are closely linked. Glucosamine directly activates hexosamine biosynthesis pathway.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Hind-limb ischemia in endothelial nitric oxide synthase knockout (eNOS\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ) and BALB\/c mice was used. Glucosamine (600 \u03bcg\/g per day) was injected intraperitoneally. Blood flow recovery was assessed using laser Doppler perfusion imaging and angiogenesis was studied by CD31 immunostaining. In vitro, human umbilical vein ECs and mouse microvascular ECs with glucosamine, L-glucose, or vascular endothelial growth factor (VEGF\n              <jats:sub>165<\/jats:sub>\n              a) were tested under hypoxia and serum starvation. Cell Counting Kit\u20138, tube formation, intracellular reactive oxygen species, electric cell\u2013substrate impedance sensing, and fluorescein isothiocyanate dextran permeability were assessed. Glycolysis and oxidative phosphorylation were assessed by seahorse assay. Gene expression was assessed using RNA sequencing, real-time quantitative polymerase chain reaction, and Western blot. Human muscle biopsies from patients with peripheral arterial disease were assessed for EC O-GlcNAcylation before and after supervised exercise versus standard medical care.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              On day 3 after hind-limb ischemia, glucosamine-treated versus control eNOS\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice had less necrosis (n=4 or 5 per group). Beginning on day 7 after hind-limb ischemia, glucosamine-treated versus control BALB\/c mice had higher blood flow, which persisted to day 21, when ischemic muscles showed greater CD31 staining per muscle fiber (n=8 per group). In vitro, glucosamine versus L-glucose ECs showed improved survival (n=6 per group) and tube formation (n=6 per group). RNA sequencing of glucosamine versus L-glucose ECs showed increased amino acid metabolism (n=3 per group). That resulted in increased oxidative phosphorylation (n=8\u201312 per group) and serine biosynthesis pathway without an increase in glycolysis or pentose phosphate pathway genes (n=6 per group). This was associated with better barrier function (n=6\u20138 per group) and less reactive oxygen species (n=7 or 8 per group) compared with activating glycolysis by VEGF\n              <jats:sub>165<\/jats:sub>\n              a. These effects were mediated by activating transcription factor 4, a driver of exercise-induced angiogenesis. In muscle biopsies from humans with peripheral arterial disease, EC\/O-GlcNAcylation was increased by 12 weeks of supervised exercise versus standard medical care (n=6 per group).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>In cells, mice, and humans, activation of hexosamine biosynthesis pathway by glucosamine in peripheral arterial disease induces an \u201cexercise-like\u201d angiogenesis and offers a promising novel therapeutic pathway to treat this challenging disorder.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.069580","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T09:19:39Z","timestamp":1725959979000},"page":"1702-1719","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Glucosamine-Mediated Hexosamine Biosynthesis Pathway Activation Uses ATF4 to Promote \u201cExercise-Like\u201d Angiogenesis and Perfusion Recovery in PAD"],"prefix":"10.1161","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4306-4632","authenticated-orcid":true,"given":"Suhib","family":"Alhusban","sequence":"first","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Nofal","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7244-5517","authenticated-orcid":true,"given":"Anita","family":"Kovacs-Kasa","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2615-3788","authenticated-orcid":true,"given":"Taylor C.","family":"Kress","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Murat","family":"Koseoglu","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2919-5329","authenticated-orcid":true,"given":"Abdelrahman A.","family":"Zaied","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."},{"name":"Department of Medicine (A.A.Z., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0184-3830","authenticated-orcid":true,"given":"Eric J.","family":"Belin de Chantemele","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-8243","authenticated-orcid":true,"given":"Brian H.","family":"Annex","sequence":"additional","affiliation":[{"name":"Vascular Biology Center (S.A., M.N., A.K.-K., T.C.K., M.M.K., A.A.Z., E.J.B.d.C., B.H.A.), Medical College of Georgia at Augusta University."},{"name":"Department of Medicine (A.A.Z., B.H.A.), Medical College of Georgia at Augusta University."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.4239\/wjd.v6.i7.961"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318535"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","unstructured":"Benjamin EJ Virani SS Callaway CW Chamberlain AM Chang AR Cheng S Chiuve SE Cushman M Delling FN Deo R et al. 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