title: Atrial natriuretic peptide reduces vascular leakage and choroidal neovascularization.
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 micromol/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.
authors.affiliation: Angiogenesis Laboratory, Massachusetts Eye & Ear Infirmary, and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lara-Castillo
authors.forename: Souska
authors.initials: S
authors.lastname: Zandi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ito
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Haicheng
authors.initials: H
authors.lastname: She
authors.forename: Muna
authors.initials: M
authors.lastname: Ahmed
authors.forename: Sonja
authors.initials: S
authors.lastname: Frimmel
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Ablonczy
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001813:Blood-Retinal Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D020256:Choroidal Neovascularization / Q000378:metabolism*; D006801:Humans; D008297:Male; D051381:Rats; D012171:Retinal Vessels / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
chemical_list: D042461:Vascular Endothelial Growth Factor A; D009320:Atrial Natriuretic Factor