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Novel TIE‐2 phosphatase inhibitors restore angiogenesis in RAS suppressed Sprague Dawley rats
Author(s) -
Stodola Timothy,
Greene Andrew
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1031.8
Subject(s) - angiogenesis , chemistry , endocrinology , medicine , receptor , dephosphorylation , alkaline phosphatase , pharmacology , phosphatase , enzyme , biochemistry
The TIE‐2 receptor binds with Angiopoietins (Ang‐1), and activation triggers signaling pathways associated with endothelial cell migration, proliferation, survival, permeability, sprouting and tube formation. Previous results showed novel HPTPβ inhibitors could selectively inhibit dephosphorylation of the TIE‐2 receptor. The goal of this study was to determine if these drugs could restore angiogenesis in Renin‐Angiotensin System (RAS) suppressed Sprague Dawley (SD) rats. Seven week old SD rats were placed on 4% NaCl diet to suppress RAS. Electrical stimulators were implanted to intermittently stimulate the peroneal nerve in one hind leg, contracting the Tibialis Anterior (TA) and Extensor Digitorum Longus (EDL) muscles for 8 hours/day for 7 days while they were injected with AKB‐9328 (15 mg/kg) or AKB‐9778 (5, 7.5, 10, 15, 25 mg/kg) s.c. b.i.d. High salt animals receiving vehicle had a 0.9% increase in vessel density, while low salt controls had a 13.6% increase in vessel density. Animals with doses at and above 10 mg/kg of either drug showed significant increases in vessel density, while doses of 5 and 7.5 mg/kg did not show significant increases in vessel density. These data show inhibition of TIE‐2 receptor dephosphorylation can restore physiological angiogenesis in high salt inhibited rats. Supported by Akebia Theraputics, Inc, project AG‐08‐001 and AG‐09‐001.