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

Abstract

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 stretchmagnitude-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). VEGFNAb 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.

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…VEGF is thought to have a central role in increased vascular retinal permeability and in the development of intraocular neovascularization in DR. 31 The fact that retinal pigment epithelial cells respond to stretch by increasing the expression of VEGF was first demonstrated by Seko et al 32 This finding was confirmed and extended by Suzuma et al, 33 who showed that bovine retinal endothelial and pericyte cells exposed to cyclic stretch increase the expression of VEGF and its receptor, both protein and mRNA. Later, it was suggested that stretch-induced retinal VEGF expression was mediated by phosphatidylinositol 3-kinase and protein kinase C. 34 Furthermore, it has been demonstrated that stretch induces apoptosis in porcine retinal pericytes that may be mediated by oxidative stress.…”

Diabetic retinopathy

“…Captopril and atenolol reduced the cumulative risk of microvascular end-points to the same extent, suggesting an effect related to blood pressure lowering rather than properties intrinsic to the agents. Mechanisms proposed for hypertension-induced worsening of DR include endothelial shear stress and stretchrelated release of VEGF from the vessel wall [95], consequent to impaired autoregulation of retinal blood flow with increasing perfusion pressures [9].…”

VEGF-C mediates cyclic pressure-induced endothelial cell proliferation

“…Different VEGF ligands have been associated with other mechanical forces; for example, VEGF-A transcripts were elevated in bovine endothelial cells exposed to 9% cyclic stretch of the substrate for 9 h (25). Although the DNA microarrays used in the present study contained oligonucleotide probes for VEGF-A, neither rigorous Affymetrix (Fig.…”