Abstract
Abstract: :
It has been reported that treatment with angiotensin converting enzyme inhibitors ameliorates diabetic retinopathy. It is not clear whether or not angiotensin II (Ang II) is angiogenic. Purpose: To test: 1) whether Ang II is capable of inducing neovascularization, and if so which Ang II receptor (AT) subtype mediates the responses, and 2) whether VEGF is involved. Methods: Angiogenic activity was studied using the rat cornea pocket angiogenesis assay. Hydron pellets containing the substances under study were implanted into the corneal stroma adjacent to the temporal limbus. Rats were divided into the following groups: 1) Ang II (20 µg/pellet), 2) Ang II in combination with the AT1 antagonist losartan or the AT2 antagonist PD123319, 3) VEGF (250 ng/pellet), either alone or in combination with Ang II, and, 4) Ang II in combination with the VEGF receptor inhibitor, SU5416. Seven days after pellet implantation, the rats were perfused with India ink through the left ventricle, thus allowing visualization of corneal neovascularization. Whole-mount cornea preparations were photographed, digitized and vessel lengths (pixels), and area occupied by vessels (pixels2), were measured by image analysis software. Results: Ang II increased vessel length and vessel area from 5.2 5.0 and 70 60 (control) to 61.3 15, and 7450 2600, respectively. Ang II-induced neovascularization was inhibited in 80% by the specific AT1 receptor antagonist Losartan, while PD123319 had no effects. The selective VEGF receptor flk-1/KDR inhibitor SU5416 inhibited Ang II-induced neovascularization in 50%. VEGF increased vessels length to 5817 and area to 68003120. When Ang II and VEGF were co-administered, vessel length and vessel area were further increased to 136.2 4.0 and 20041 4185. VEGF mRNA in cornea homogenates was increased in ∼20 % by treatment with either Ang II or VEGF and ∼100% by co-administration of Ang II and VEGF. Conclusions: Ang II induces AT1 and VEGF receptor-mediated neovascularization and augments VEGF-induced neovascularization and upregulation of VEGF mRNA. Thus, Ang II may contribute to regulation of angiogenic events by modulating VEGF-induced responses.
Keywords: 566 retinal neovascularization • 423 growth factors/growth factor receptors • 388 diabetic retinopathy