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.