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Cyclic Stretch and Hypertension Induce Retinal Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor—2

Potential Mechanisms for Exacerbation of Diabetic Retinopathy by Hypertension

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.

Address correspondence and reprint requests to Lloyd Paul Aiello, MD, PhD, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02115. E-mail: lpaiello{at}joslin.harvard.edu .

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 ± 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—dependent manner. Exposure to 9% cyclic stretch increased KDR mRNA expression 8.7 ± 2.9-fold (P = 0.011) after 9 h and KDR protein concentration 1.8 ± 0.3-fold (P = 0.005) after 12 h. Stretched-induced VEGF responses were similar. Scatchard binding analysis demonstrated a 180 ± 40% (P = 0.032) increase in high-affinity VEGF receptor number with no change in affinity. Cyclic stretch increased basal thymidine uptake 60 ± 10% (P < 0.001) and VEGF-stimulated thymidine uptake by 2.6 ± 0.2-fold (P = 0.005). VEGF-NAb reduced cyclic stretch—induced thymidine uptake by 65%. Stretched-induced KDR expression was not inhibited by AT1 receptor blockade using candesartan. Hypertension increased retinal KDR expression 67 ± 42% (P < 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.

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