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

Systemic hypertension exacerbates diabetic retinopathy and other coexisting ocular disorders through mechanisms that remain largely unknown. Increased vascular permeability and intraocular neovascularization characterize thes e conditions and are complications primarily mediated by vascular endotheli al growth factor (VEGF). Because systemic hypertension increases vascular s tretch, 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 cy clic stretch and in spontaneously hypertensive rat (SHR) retina. A single e xposure 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 cp m continuously accumulated KDR mRNA in a transcriptionally mediated, time-d ependent and stretch-magnitude-dependent manner. Exposure to 9% cyclic stre tch increased KDR mRNA expression 8.7 +/- 2.9-fold (P = 0.011) after 9 h an d KDR protein concentration 1.8 +/- 0.3-fold (P = 0.005) after 12 h. Stretc hed-induced VEGF responses were similar. Scatchard binding analysis demonst rated a 180 +/- 40%, (P = 0.032) increase in high-affinity VEGF receptor nu mber with no change in affinity. Cyclic stretch increased basal thymidine u ptake 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 u ptake by 65%. Stretched-induced KDR expression was not inhibited by AT1 rec eptor blockade using candesartan. Hypertension increased retinal. KBR expre ssion 67 +/- 42% (P < 0.05) in SHR rats compared with normotensive WKY cont rol 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 me chanism 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 hype rtensive retinopathy and/or ameliorating the deleterious effects of coexist ent hypertension on VEGF-associated disorders such as diabetic retinopathy.