Atrial natriuretic peptide reduces vascular leakage and choroidal neovascularization

Nuria Lara-Castillo, Souska Zandi, Shintaro Nakao, Yasuhiro Ito, Kousuke Noda, Haicheng She, Muna Ahmed, Sonja Frimmel, Zsolt Ablonczy, Ali Hafezi-Moghadam

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Abstract

Atrial natriuretic peptide (ANP) is a hormone with diuretic, natriuretic, and vasodilatory properties. ANP blocks vascular endothelial growth factor (VEGF) production and signaling in vitro; however, its role in vascular leakage and angiogenesis is unknown. In vitro, retinal barrier permeability (transepithelial electrical resistance (TEER)) was measured in cultured retinal endothelial (HuREC) and retinal epithelial (ARPE-19) cells with VEGF (10 ng/ml), ANP (1 pM to 1 μmol/L), and/or isatin, an ANP receptor antagonist. In vivo, blood-retinal barrier (BRB) leakage was studied using the Evans Blue dye technique in rats treated with intravitreal injections of ANP, VEGF, or vehicle. Choroidal neovascularization was generated by laser injury, and 7 days later, lesion size and leakage was quantitated. ANP significantly reversed VEGF-induced BRB TEER reduction in both HuREC and ARPE-19 cells, modeling the inner and the outer BRB, respectively. Isatin, a specific ANP receptor antagonist, reversed ANP's effect. ANP reduced the response of ARPE-19 cells to VEGF apically but not basolaterally, suggesting polarized expression of the ANP receptors in these cells. ANP's TEER response was concentration but not time dependent. In vivo, ANP significantly reduced VEGF-induced BRB leakage and the size of laser-induced choroidal neovascularization lesions. In sum, ANP is an effective inhibitor of VEGF-induced vascular leakage and angiogenesis in vivo. These results may lead to new treatments for ocular diseases where VEGF plays a central role, such as age-related macular degeneration or diabetic retinopathy.

Original languageEnglish
Pages (from-to)2343-2350
Number of pages8
JournalAmerican Journal of Pathology
Volume175
Issue number6
DOIs
Publication statusPublished - Jan 1 2009
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Lara-Castillo, N., Zandi, S., Nakao, S., Ito, Y., Noda, K., She, H., ... Hafezi-Moghadam, A. (2009). Atrial natriuretic peptide reduces vascular leakage and choroidal neovascularization. American Journal of Pathology, 175(6), 2343-2350. https://doi.org/10.2353/ajpath.2009.090439