{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:00:01Z","timestamp":1789376401192,"version":"build-2803163510"},"reference-count":101,"publisher":"American Diabetes Association","issue":"2","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,2,1]]},"abstract":"<jats:p>Systemic hypertension exacerbates diabetic retinopathy and other coexisting ocular disorders through mechanisms that remain largely unknown. Increased vascular permeability and intraocular neovascularization characterize these conditions and are complications primarily mediated by vascular endothelial growth factor (VEGF). Because systemic hypertension increases vascular stretch, we evaluated the expression of VEGF, VEGF-R2 (kinase insert domain-containing receptor [KDR]), and VEGF-R1 (fms-like tyrosine kinase[Flt]) in bovine retinal endothelial cells (BRECs) undergoing clinically relevant cyclic stretch and in spontaneously hypertensive rat (SHR) retina. A single exposure to 20% symmetric static stretch increased KDR mRNA expression 3.9 \u00b1 1.1-fold after 3 h (P = 0.002), with a gradual return to baseline within 9 h. In contrast, BRECs exposed to cardiac-profile cyclic stretch at 60 cpm continuously accumulated KDR mRNA in a transcriptionally mediated, time-dependent and stretch-magnitude\u2014dependent manner. Exposure to 9% cyclic stretch increased KDR mRNA expression 8.7 \u00b12.9-fold (P = 0.011) after 9 h and KDR protein concentration 1.8\u00b1 0.3-fold (P = 0.005) after 12 h. Stretched-induced VEGF responses were similar. Scatchard binding analysis demonstrated a 180 \u00b140% (P = 0.032) increase in high-affinity VEGF receptor number with no change in affinity. Cyclic stretch increased basal thymidine uptake 60\u00b1 10% (P &amp;lt; 0.001) and VEGF-stimulated thymidine uptake by 2.6 \u00b1 0.2-fold (P = 0.005). VEGF-NAb reduced cyclic stretch\u2014induced thymidine uptake by 65%. Stretched-induced KDR expression was not inhibited by AT1 receptor blockade using candesartan. Hypertension increased retinal KDR expression 67 \u00b1 42% (P &amp;lt;0.05) in SHR rats compared with normotensive WKY control animals. When hypertension was reduced using captopril or candesartan, retinal KDR expression returned to baseline levels. VEGF reacted similarly, but Flt expression did not change. These data suggest a novel molecular mechanism that would account for the exacerbation of diabetic retinopathy by concomitant hypertension, and may partially explain the principal clinical manifestations of hypertensive retinopathy itself. Furthermore, these data imply that anti-VEGF therapies may prove therapeutically effective for hypertensive retinopathy and\/or ameliorating the deleterious effects of coexistent hypertension on VEGF-associated disorders such as diabetic retinopathy.<\/jats:p>","DOI":"10.2337\/diabetes.50.2.444","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"444-454","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":107,"title":["Cyclic Stretch and Hypertension Induce Retinal Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor\u20142"],"prefix":"10.2337","volume":"50","author":[{"given":"Izumi","family":"Suzuma","sequence":"first","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuaki","family":"Hata","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Clermont","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Pokras","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Rook","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Suzuma","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward P.","family":"Feener","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd Paul","family":"Aiello","sequence":"additional","affiliation":[{"name":"From the Research Division (I.S., Y.H., F.P., S.L.R., K.S., E.P.F.,L.P.A.) and Beetham Eye Institute (A.C., L.P.A.), Joslin Diabetes Center; and the Department of Ophthalmology (L.P.A.), Harvard Medical School, Boston,Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031208090202100_REF1","doi-asserted-by":"crossref","unstructured":"Klein R, Klein BE, Moss SE, Cruickshanks KJ: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes (see comments). Ophthalmology\u2008105: 1801-1815,1998","DOI":"10.1016\/S0161-6420(98)91020-X"},{"key":"2022031208090202100_REF2","doi-asserted-by":"crossref","unstructured":"Wan Nazaimoon WM, Letchuman R, Noraini N, Ropilah AR, Zainal M,Ismail IS, Wan Mohamad WB, Faridah I, Singaraveloo M, Sheriff IH, Khalid BA:Systolic hypertension and duration of diabetes mellitus are important determinants of retinopathy and microalbuminuria in young diabetics. Diabetes Res Clin Pract\u200846:213-221, 1999","DOI":"10.1016\/S0168-8227(99)00095-9"},{"key":"2022031208090202100_REF3","doi-asserted-by":"crossref","unstructured":"Agardh CD, Agardh E, Torffvit O: The association between retinopathy, nephropathy, cardiovascular disease and long-term metabolic control in type 1 diabetes mellitus: a 5-year follow-up study of 442 adult patients in routine care. Diabetes Res Clin Pract\u200835: 113-121,1997","DOI":"10.1016\/S0168-8227(97)01386-7"},{"key":"2022031208090202100_REF4","doi-asserted-by":"crossref","unstructured":"Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D, Bourguignon C, Harpey C, Brault Y, Coste M, Moccatti D, Bourgeois H:Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol\u200882: 996-1002,1998","DOI":"10.1136\/bjo.82.9.996"},{"key":"2022031208090202100_REF5","doi-asserted-by":"crossref","unstructured":"Goldberg J, Flowerdew G, Smith E, Brody JA, Tso MO: Factors associated with age-related macular degeneration: an analysis of data from the first National Health and Nutrition Examination Survey. Am J Epidemiol\u2008128:700-710, 1988","DOI":"10.1093\/oxfordjournals.aje.a115023"},{"key":"2022031208090202100_REF6","doi-asserted-by":"crossref","unstructured":"Kahn HA, Leibowitz HM, Ganley JP, Kini MM, Colton T, Nickerson RS,Dawber TR: The Framingham Eye Study. II. Association of ophthalmic pathology with single variables previously measured in the Framingham Heart Study. Am J Epidemiol\u2008106:33-41, 1977","DOI":"10.1093\/oxfordjournals.aje.a112429"},{"key":"2022031208090202100_REF7","doi-asserted-by":"crossref","unstructured":"Abdelsalam A, Del Priore L, Zarbin MA: Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol\u200844: 1-29,1999","DOI":"10.1016\/S0039-6257(99)00072-7"},{"key":"2022031208090202100_REF8","doi-asserted-by":"crossref","unstructured":"Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Macular Photocoagulation Study Group. Arch Ophthalmol\u2008115:741-747, 1997","DOI":"10.1001\/archopht.1997.01100150743009"},{"key":"2022031208090202100_REF9","unstructured":"National Society to Prevent Blindness: Data Analysis. Vision Problems in the US: Facts and Figures 1980. Schaumburg,IL, National Society to Prevent Blindness, 1980"},{"key":"2022031208090202100_REF10","doi-asserted-by":"crossref","unstructured":"Aiello LP, Gardner TW, King GL, Blankenship GW, Cavallerano J,Ferris FL 3rd, Klein R: Diabetic retinopathy (Technical Review). Diabetes Care\u200821:143-156, 1998","DOI":"10.2337\/diacare.21.1.143"},{"key":"2022031208090202100_REF11","doi-asserted-by":"crossref","unstructured":"Rosenn B, Miodovnik M, Kranias G, Khoury J, Combs CA, Mimouni F,Siddiqi TA, Lipman MJ: Progression of diabetic retinopathy in pregnancy:association with hypertension in pregnancy. Am J Obstet Gynecol\u2008166:1214-1218, 1992","DOI":"10.1016\/S0002-9378(11)90608-5"},{"key":"2022031208090202100_REF12","doi-asserted-by":"crossref","unstructured":"Roy MS: Diabetic retinopathy in African Americans with type 1 diabetes: the New Jersey 725. II. Risk factors. Arch Ophthalmol\u2008118:105-115, 2000","DOI":"10.1001\/archopht.118.1.105"},{"key":"2022031208090202100_REF13","doi-asserted-by":"crossref","unstructured":"U.K. Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:UKPDS 38. BMJ\u2008317:703-713, 1998 (Erratum appears in BMJ 318:29, 1999)","DOI":"10.1136\/bmj.317.7160.703"},{"key":"2022031208090202100_REF14","unstructured":"Le Floch JP, Christin S, Bertherat J, Perlemuter L, Hazard J: Blood pressure and microvascular complications in type 1 (insulin dependent)diabetic patients without hypertension. Diabetes Metab\u200816: 26-29,1990"},{"key":"2022031208090202100_REF15","doi-asserted-by":"crossref","unstructured":"El-Asrar AM, Al-Rubeaan KA, Al-Amro SA, Kangave D, Moharram OA:Risk factors for diabetic retinopathy among Saudi diabetics. Int Ophthalmol\u200822:155-161, 1998","DOI":"10.1023\/A:1006240928938"},{"key":"2022031208090202100_REF16","doi-asserted-by":"crossref","unstructured":"Lopes de Faria JM, Jalkh AE, Trempe CL, McMeel JW: Diabetic macular edema: risk factors and concomitants. 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